Gastric Subtypes Research Articles

Abstract B091: Spatial Transcriptomics Unveils Intraductal Papillary Mucinous Neoplasm Heterogeneity: From Novel Clusters to Immune Dynamics

Abstract Intraductal papillary mucinous neoplasms (IPMNs), a common precursor to pancreatic ductal adenocarcinoma, present as a spectrum of benign indolent behavior and progression to invasive carcinoma, which highlights the importance of identifying biomarkers of IPMN progression. This study utilized whole transcriptome spatial transcriptomics to define the molecular characteristics of Epithelial, Immune, and Fibroblast cell populations of the three distinct histological sub-types of IPMN to understand the dynamics between the cell types and identify biomarkers of neoplastic progression. Fifty-two surgically resected IPMN cores from 21 patients with resected IPMNs comprising 24 Gastric, 14 Intestinal, and 14 Pancreaticobiliary with a distribution of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and Invasive carcinoma (IC) were analyzed. Epithelial, Immune, and Fibroblast components were analyzed using the GeoMx spatial profiler. Unsupervised hierarchical clustering of epithelial areas of interest (AOI) identified 3 distinct clusters demonstrating a spectrum of molecular phenotypes in IPMN that were correlated with the three histological subtypes. Comparing the gene expression profile based on the shared genes expressed on all three subtypes, the Intestinal type tends to have an overexpression of genes whereas the Pancreaticobiliary represents a repressed phenotype relative to the Gastric phenotype. Supervised clustering using Moffitt’s classifier to identify the Epithelial-Mesenchymal transition demonstrates the Pancreaticobiliary subtype to be more Basal-like versus the Gastric and Intestinal inclined towards the classical phenotype. Supervised clustering based on the degree of dysplasia within the epithelial compartments of each of these subtypes, demonstrated a spectrum of molecular heterogeneity and identified biomarkers specific to High-Grade dysplasia in the Gastric and Intestinal subtype. Immune AOI deconvolution analysis demonstrated that Tregs were associated with Pancreaticobiliary, Macrophage enrichment associated with the Intestinal phenotype, while there is enrichment of CD8 T-cell and CD4 T-cell gene signatures associated with the Gastric subtype. Fibroblast AOI analyses demonstrated heterogenous myCAF- iCAF signatures between the subtypes. In summary, Spatial whole transcriptome analysis of IPMN identifies molecular signatures in epithelial and immune compartments that differentiate between the three histological subtypes of IPMN and helps understand their progression from Low-grade dysplasia to High-grade dysplasia. Citation Format: Amaya Pankaj, Michael J Raabe, Yuhui Song, Bidish K Patel, Katherine Xu, Joshua R Kocher, Nicholas J Caldwell, Maria L Ganci, Linda T Nieman, Mari Mino-Kenudson, Vikram Deshpande, Nabeel Bardeesy, Carlos Fernandez-Del Castillo, Martin J Aryee, David T Ting, Yasmin G Hernandez-Barco. Spatial Transcriptomics Unveils Intraductal Papillary Mucinous Neoplasm Heterogeneity: From Novel Clusters to Immune Dynamics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B091.

Precursor Epithelial Subtypes of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasms (A-IPMN): Clinicopathological Features, Recurrence and Response to Adjuvant Chemotherapy

BackgroundThe clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown.MethodsClincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010–2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis.ResultsIn total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31–1.01; p = 0.058].ConclusionsGastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype.

Clinicopathological features and cancer transcriptomic profiling of poorly cohesive gastric carcinoma subtypes.

Gastric poorly cohesive carcinoma (PCC) manifests with a diffuse pattern and diverse tumor cell morphologies, often indicating a more unfavorable prognosis. Recent consensus has reclassified PCC based on the proportion of signet-ring cells (SRCs) in tumors for research purposes. The two most distinct subtypes, poorly cohesive carcinoma not otherwise specified (PCC-NOS) and signet-ring cell carcinoma (SRCC), are characterized by less than 10% and more than 90% SRCs, respectively. However, research comparing the clinicopathological and transcriptomic differences between these subtypes remains limited. In this study, we conducted a comparative analysis of clinicopathological features in 55 advanced-stage PCCs, consisting of 43 PCC-NOS and 12 SRCC cases. Subsequently, 12 PCC-NOS and 5 SRCC cases were randomly selected for initial cancer-related gene expression profiling and pathway enrichment analysis using the GeoMx digital spatial profiler, followed by validation in a separate validation group comprising 16 PCC-NOS and 6 SRCC cases. These transcriptomic findings were then correlated with tumor morphology and clinicopathological data. PCC-NOS cases exhibited larger tumor size, a higher prevalence of pathological N3 disease, and a worse 1-year progression-free survival rate compared to SRCC cases. Clustering of PCC-NOS and SRCC was successfully achieved using the GeoMx Cancer Transcriptome Atlas. Among all studied genes, only MMP7 showed differential expression, with its overexpression significantly associated with the PCC-NOS subtype, increased perineural invasion, and earlier disease progression. Pathway analysis revealed significantly enriched pathways in PCC-NOS related to vesicle-mediated transport, adaptive immune systems, oncogenic signaling, and extracellular matrix organization, while SRCC displayed significant enrichment in pathways associated with respiratory electron transport and the cell cycle. In conclusion, this study compares and correlates clinicopathological features and transcriptomic data between PCC-NOS and SRCC at advanced stages, employing the latest consensus classification and a novel platform for analysis.

A Review of Type 1 and Type 2 Intraductal Papillary Neoplasms of the Bile Duct.

Intraductal papillary neoplasm of the bile duct (IPNB) is a heterogeneous disease similar to intraductal papillary mucinous neoplasm of the pancreas. These lesions have been recognized as one of the three major precancerous lesions in the biliary tract since 2010. In 2018, Japanese and Korean pathologists reached a consensus, classifying IPNBs into type l and type 2 IPNBs. IPNBs are more prevalent in male patients in East Asia and are closely related to diseases such as cholelithiasis and schistosomiasis. From a molecular genetic perspective, IPNBs exhibit early genetic variations, and different molecular pathways may be involved in the tumorigenesis of type 1 and type 2 IPNBs. The histological subtypes of IPNBs include gastric, intestinal, pancreaticobiliary, or oncocytic subtypes, but type 1 IPNBs typically exhibit more regular and well-organized histological features than type 2 IPNBs and are more commonly found in the intrahepatic bile ducts with abundant mucin. Due to the rarity of these lesions and the absence of specific clinical and laboratory features, imaging is crucial for the preoperative diagnosis of IPNB, with local bile duct dilation and growth along the bile ducts being the main imaging features. Surgical resection remains the optimal treatment for IPNBs, but negative bile duct margins and the removal of lymph nodes in the hepatic hilum significantly improve the postoperative survival rates for patients with IPNBs.

O77: Invasive intraductal oncocytic papillary neoplasms (IOPN) and adenocarcinomas arising from Intraductal papillary mucinous neoplasms (IPMN): adjuvant chemotherapy, patterns of recurrence and survival

Abstract Introduction Invasive intraductal oncocytic papillary neoplasms (IOPNs) are extremely rare and are increasingly being recognised as their own entity, distinct from intraductal papilliary mucinous neoplasism subtypes (IPMN). Their clinicopathologic behaviour, recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown compared to adenocarcinomas arising from IPMN but were investigated in the present study. Methods Patients undergoing pancreatic resection between 2010-2020 for invasive IOPNs and adenocarcinoma arising from IPMNs were identified retrospectively from 18 academic pancreatic centers worldwide. Survival analyses were conducted to compare outcome measures between IOPNs and IPMN precursor epithelial subtypes and invasive components. Results Of the 459 patients with invasive IOPN/IPMNs, 20 patients had an invasive IOPN (median age,69; male,n=11), the majority of which were in the pancreatic head (75%) and underwent either a Whipples procedure (40%) or PPPD (35%). After a median follow-up of 6 years, 45% of invasive IOPNs developed recurrence (1-year,30.0%; 5-year,69.2%) and 40% survived follow-up (2-year survival 55.0%, 5-year survival, 30.8%). Recurrence rates and survival of invasive IOPNs were higher than colloid IPMNs (n=64) (p=0.031 and p=0.007) and comparable with ductal IPMNs (n=331) as well as gastric (n=54) and pancreatobiliary (n=111) IPMN subtypes. Invasive IOPN had significantly lower cancer-specific survival compared to colloid carcinomas (p<0.001). Adjuvant chemotherapy did not improve rates of recurrence in invasive IOPN and IPMN subtypes (p>0.05). Conclusions Invasive IOPNs are more aggressive than previously suspected and should be regarded as their own entity. Adjuvant chemotherapy does not reduce rates of recurrence regardless of neoplasm type.

Pathological survey of precursor lesions in cholangiocarcinoma.

To clarify the pathological significance of two precursors (high-grade biliary intraepithelial neoplasm [BilIN] and intraductal papillary neoplasm of bile duct [IPNB]) in cholangiocarcinomas (CCAs). Ninety-one cases of CCA (47 distal CCAs [dCCAs], 31 perihilar CCAs [pCCAs] and 13 intrahepatic CCAs of large duct type [LD-iCCAs]) were examined for their association with precursors. Neoplastic intraepithelial lesions without underlying infiltrating carcinoma in the surrounding mucosa of CCAs were considered to reflect high-grade BilIN. High-grade BilIN and IPNB were subdivided into gastric, biliary, intestinal and oncocytic subtypes, while CCAs were subdivided into gastrobiliary, intestinal and oncocytic subtypes. The postoperative overall survival (OS) was examined. Fifty-four and 8 of 91 CCAs were associated with high-grade BilIN and IPNB, respectively, while these precursors were unidentifiable in the remaining CCAs. A majority of CCAs were of the gastrobiliary subtype, while the intestinal subtype was occasionally detected, and the oncocytic subtype was rare. CCAs with high-grade BilIN showed a similar postoperative OS to CCAs without precursors, while CCAs with IPNB showed a favorable postoperative OS compared to CCAs without precursors. CCAs were frequently associated with precursors; high-grade BilIN may be a major precursor and IPNB a minor one. CCAs with IPNB showed a favorable postoperative OS compared to CCAs with high-grade BilIN.

Transcriptional activity of PTX3 gene in diffuse gastric carcinoma subtype

Transcriptional activity of PTX3 gene in diffuse gastric carcinoma subtype

Excurve and Emit Lobular Endocervical Glandular Hyperplasia

Lobular endocervical glandular hyperplasia of uterine cervix is a benign, exceptional lesion with a characteristic proliferation of miniature, spherical glands accompanied by gastric type differentiation. The discrete lobules incriminate upper endocervical canal of predominantly premenopausal women. Lobular endocervical glandular hyperplasia and gastric subtypes of cervical glandular lesions appear non concurrent to persistent infection with high risk variants of human papilloma virus (HPV). Cytological examination depicts mono-layered sheets of tall, columnar, mucinous cells demonstrating smooth nuclear outline with absent cellular or nuclear atypia or mitotic figures. Papanicolaou stained smears exemplify extracellular or intracellular, golden yellow mucin, indicative of gastric subtype of cellular differentiation. The well-defined lobular or acinar lesion is comprised of a centric crypt with circumscribing glandular articulations and miniature, spherical cysts which configure a floret-like pattern. Centric and peripheral glands are layered with columnar epithelial cells pervaded with pale, eosinophilic cytoplasm, bland, miniature, basal nuclei with mild nuclear atypia. Atypical cytological and architectural features may progress into the malignant ‘atypical lobular endocervical glandular hyperplasia’, currently contemplated as a category of gastric type adenocarcinoma in situ (GAIS). The lesion is immune reactive to pyloric gland mucin (HIK1083), MUC6, PAX2 or chromogranin A. Lobular endocervical glandular hyperplasia of uterine cervix requires segregation from neoplasms such as human papilloma virus (HPV) independent endocervical adenocarcinoma, gastric type, pyloric type metaplasia, gastric type adenocarcinoma in situ, type A tunnel clusters, micro glandular hyperplasia and mesonephric remnants or mesonephric hyperplasia of uterine cervix. Lesions detected upon surgical tissue sampling, cervical loop electrosurgical excision procedure (LEEP) or conisation may be optimally managed with total abdominal hysterectomy

Tralucent and Pellucid-Clear Cell Adenocarcinoma Uterine Cervix

Clear cell adenocarcinoma of uterine cervix is predominantly comprised of clear cells or hobnail cells articulating distinct architectural patterns as solid, tubulocystic or papillary. Tumour cell cytoplasm is clear, eosinophilic with intracytoplasmic hyaline globules and enhanced nuclear grade. A historic association with intrauterine diethylstilbestrol (DES) exposure is enunciated. Sporadic overexpression of p53 tumour suppressor gene may be observed. Neoplasm manifests with vaginal bleeding, postcoital bleeding or abnormal vaginal discharge. Cytological smears exhibit sheets, clusters or papillae of tumour cells permeated with delicate, vacuolated, glycogen rich or finely granular cytoplasm, enlarged, pale, spherical nuclei with prominent nucleoli or naked nuclei with tigroid background composed of granular, reticulated substance. Clear cell adenocarcinoma appears immune reactive to pan-cytokeratin as AE1 / AE3, CAM5.2, CK7, CK8, CK18, CK19, HNF1β, Napsin A, Ki67 or epithelial membrane antigen (EMA). Tumefaction requires segregation from neoplasms such as microglandular hyperplasia, Arias-Stella reaction, primary alveolar soft part sarcoma, mesonephric adenocarcinoma, metastatic clear cell renal cell carcinoma, endometrioid carcinoma, serous carcinoma, squamous cell carcinoma, urothelial carcinoma, adenosis, endometrioid adenocarcinoma with clear cell or secretory change, gastric subtype of endocervical adenocarcinoma or yolk sac tumours of uterine cervix. Neoplasm may be preliminarily subjected to radical hysterectomy with pelvic lymphadenectomy or fertility sparing radical trachelectomy.

Negative correlation between the nuclear size and nuclear Lamina component Lamin A in intraductal papillary mucinous neoplasms of the pancreas.

Background: The nuclear laminar protein Lamin A and inner nuclear membrane protein Emerin plays important role in sustaining nuclear structure. However, They have not investigated the significance of these proteins for development of pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods: We examined pancreatic IPMN specimens for nuclear morphology and nuclear protein expression pattern of Lamin A and Emerin. Forty-two IPMN specimens were included, with 30 classified as intraductal papillary mucinous adenoma (IPMA) and 12 as intraductal papillary mucinous carcinoma (IPMC). Results: Classification according to histological subtype revealed that 26 specimens were of the gastric subtype (1 IPMC case), 8 were pancreatobiliary (6 IPMC cases), 6 were intestinal (3 IPMC cases), and 2 were oncocytic (all cases were IPMC). The frequency of IPMN subtypes in this study seemed to agree with those in previous reports. We analyzed Feulgen staining sections for nuclear morphological analysis using computer-assisted image analysis. Nuclear area and perimeter were significantly larger in IPMC than in IPMA. Finally, we examined the positive ratios of Lamin A and Emerin in immunohistochemical staining sections by image analysis. We found a negative correlation between the nuclear size and Lamin A-positive ratio, which was significantly lower in IPMC than that in IPMA. However, no significant correlation was observed between nuclear size and Emerin expression was observed, and no differences were found in the Emerin-positive ratio between IPMA and IPMC. Conclusion: Our results suggest that a decreased Lamin A positive ratio induces nuclear enlargement in adenomas, which thereby induce promotion to carcinomas. Furthermore, Lamin A expression can be a reliable biomarker for distinguishing between IPMC and IPMA.

Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity

Single-cell transcriptomic profiles analysis has proposed new insights for understanding the behavior of human gastric cancer (GC). GC offers a unique model of intratumoral heterogeneity. However, the specific classes of cells involved in carcinogenetic passage, and the tumor microenvironment of stromal cells was poorly understood. We characterized the heterogeneous cell population of precancerous lesions and gastric cancer at the single-cell resolution by RNA sequencing. We identified 10 gastric cell subtypes and showed the intestinal and diffuse-type cancer were characterized by different cell population. We found that the intestinal and diffuse-type cancer cells have the differential metaplastic cell lineages: intestinal-type cancer cells differentiated along the intestinal metaplasia lineage while diffuse-type cancer cells resemble de novo pathway. We observed an enriched CCND1 mutation in premalignant disease state and discovered cancer-associated fibroblast cells harboring pro-stemness properties. In particular, tumor cells could be categorized into previously proposed molecular subtypes and harbored specific subtype of malignant cell with high expression level of epithelial-myofibroblast transition which was correlated with poor clinical prognosis. In addition to intratumoral heterogeneity, the analysis revealed different cellular lineages were responsible for potential carcinogenetic pathways. Single-cell transcriptomes analysis of gastric pre-cancerous lesions and cancer may provide insights for understanding GC cell behavior, suggesting potential targets for the diagnosis and treatment of GC.

Pathological features of pyloric gland adenoma of the gallbladder in comparison with gastric subtype of intracholecystic papillary neoplasm

Background and aimsPyloric gland adenoma (PGA) of the gallbladder is a polypoid, preinvasive epithelial neoplasm composed of uniform back-to-back, pyloric glands in a tubular configuration. Intracholecystic papillary neoplasm (ICPN), another preinvasive grossly visible neoplasm of the gallbladder, is subdividable into four subtypes, including gastric subtype. In this study, PGA was reappraised referring to gastric subtype of ICPN (gICPN). Materials and methodsPGA and gICPN pathologically defined by WHO 2019 classification were surveyed in a total of 104 cases of gallbladder epithelial neoplasms of our Hospital (2002 January to 2021 May) and were pathologically and immunohistochemically compared. ResultsPGA (7 cases) was characterized by i) a well-demarcated, polypoid lesion and ii) packed tubular components resembling pyloric glands. gICPNs (14 cases) were subdivided into i) pyloric gland predominant (2 cases), ii) foveola predominant (6 cases) and iii) mixed foveola and pyloric gland type (6 cases). gICPNs were also divided into a solitary, polypoid lesion with well demarcation from the surrounding mucosa (5 cases) and a conglomerated polypoid and granular lesions with poor demarcation (9 cases). PGA shared gross and histologic features with solitary, polypoid gICPNs, and PGA could be regarded as solitary gICPN predominantly composed of pyloric glands. Nuclear expression of β-catenin was found in 6 of 7 PGA, but absent in gICPN, including solitary, polypoid gICPN. ConclusionPGA could correspond to a solitary gICPN mainly composed of pyloric glands, but may undergo a different molecular pathway from gICPN.

Characterization of high-grade biliary intraepithelial neoplasm of the gallbladder in comparison with intracholecystic papillary neoplasm

Biliary intraepithelial neoplasm (BilIN) is characterized by a microscopically identifiable preinvasive neoplasm of the biliary tract. In this study, the high-grade BilIN of gallbladder was examined pathologically and compared with the intracholecystic papillary neoplasm (ICPN) of gallbladder. Sixteen high-grade BilINs (height <0.5cm) collected from 2297 cholecystectomies (0.7%) and another three cases (19 cases total) were examined and compared with 34 cases of ICPN (greatest diameter ≥1cm and height ≥0.5cm). High-grade BilINs were incidentally found in 11 cholecystectomies, and the remaining eight were cholecystectomized in cases with a preoperative diagnosis of carcinoma. The largest diameter ranged from 0.5 to 6cm. While 13 cases were recognized grossly as clustered granular and rough mucosa, the remaining were almost unrecognizable. Histologically, the high-grade BilINs showed intraepithelial neoplastic growth. Furthermore, they frequently showed intraepithelial replacement growth to non-neoplastic glands and cystic lesions in the gallbladder. The lesions presented with flat, wave or fold-like patterns, including tubular components. Short papillary components were also found in 13 cases. Gastric and biliary subtypes were frequent. Several foci of stromal invasion were found in the short papillary components in three cases. The lower polypoid or granular parts of conglomerated ICPNs showed intraepithelial neoplastic lesions sharing many features with high-grade BilINs with short papillary components. In conclusion, high-grade BilINs showed intraepithelial growth of neoplastic epithelia involving the mucosa. A morphologic continuum was noted between high-grade BilINs with short papillary components and conglomerated ICPNs, suggesting that conglomerated ICPNs may arise from high-grade BilINs with short papillary components.

P-171 Does metastasectomy really improve survival in gastric cancer?

Previous observational studies suggest that metastasectomy improves overall survival (OS) for patients with metastatic gastric/gastroesophageal junction cancer (mG/GEJC). However, most conclusions were based on comparisons of distinct populations, with surgery groups having favorable characteristics that could have influenced the results. All consecutive patients with mG/GEJC who underwent metastasectomy in our institution were retrospectively recruited. After, a non-metastasectomy control group, with a single site of metastasis and ECOG 0-1, was paired in a 1:1 ratio by the nearest neighbor propensity score matching method, using the following pairing categories: age at diagnosis < 60 years vs ≥ 60 years; intestinal vs diffuse subtype; synchronous vs metachronous metastasis; peritoneal vs other site of metastasis. The primary objective was to compare the overall survival (from the metastasis diagnosis to death by any cause) between the groups. Secondarily, prognostic factors associated with OS were evaluated. Time-to-event variables were analyzed by Kaplan-Meier curves and compared by Log-rank test. Cox regression was used for multivariable analysis. Between September 2007 to January 2020, 138 mG/GEJC patients were included (69 in each group). The median follow-up was 37 months. The median age at diagnosis was 54 years (31% were ≥ 60 years old); most were men (57.2%), with comorbidities (55.1%) and without malnutrition (only 8.7%). Gastric cancer (88.4%), diffuse subtype (65.2%), synchronous (77.5%) and peritoneal metastasis (65.2%) were predominant. The characteristics between the metastasectomy and the control group were well balanced, with a non-significant increased proportion of GEJC in the control group (17.4% vs 5.8%, p=0.06). Patients who underwent metastasectomy were more exposed to FLOT and less exposed to FOLFOX regimens (16.4% vs 3.0% and 37.3% vs 52.2%, respectively; p=0.048); and tended to receive triplet regimens more often (41.8% vs 29.9%; p=0.207). The median OS was superior in the metastasectomy group (26.0 vs 14.0 months; HR 0.52, 95%CI 0.35-0.78; p=0.001), as it was the median progression-free survival in first-line (12.0 vs 6.0 months; HR 0.56, 95%CI 0.39-0.80; p=0.001). The median time between the metastasectomy to death was 17.0 months (95%CI 11.4-22.6) and this was not influenced by triplet vs doublet schemes or by the metastasectomy site (peritoneal vs others, linfonodal vs others, or visceral vs non-visceral). Data were immature to evaluate the influence of type of perioperative chemotherapy on these results. Metastasectomy, FLOT regimen and ECOG 0 were independent prognostic factors for improved overall survival in multivariate analysis. Metastasectomy in gastric/gastroesophageal junction cancer was associated with improved overall survival, even when compared to a matched-paired population of metastatic patients with a favorable prognostic profile. This study reinforces the importance of considering this approach, when reasonable, for mG/GEJC patients.

Gut microbiota of patients with different subtypes of gastric cancer and gastrointestinal stromal tumors

BackgroundGastric adenocarcinoma is associated with H. pylori infection and inflammation that can result in the dysbiosis of gastric microbiota. The association of intestinal microbiota with gastric adenocarcinoma subtypes or with gastric gastrointestinal stromal tumors (GIST) is however not well known. Therefore, we performed 16S rRNA gene sequencing on DNA isolated from stool samples of Finnish patients and controls to study differences in microbiota among different histological subtypes of gastric adenocarcinoma, gastric GIST and healthy controls.ResultsWe found that gut microbiota alpha diversity was lowest in diffuse adenocarcinoma patients, followed by intestinal type and GIST patients, although the differences were not significant compared to controls. Beta-diversity analysis however showed significant differences in microbiota composition for all subtypes compared to controls. Significantly higher abundance of Enterobacteriaceae was observed in both adenocarcinoma subtypes, whereas lower abundance of Bifidobacteriaceae was seen only in diffuse adenocarcinoma and of Oscillibacter in intestinal adenocarcinoma. Both GIST and adenocarcinoma patients had higher abundance of Enterobacteriaceae and lower abundance of Lactobacillaceae and Oscillibacter while lower abundance of Lachnoclostridium, Bifidobacterium, Parabacteroides and Barnesiella was seen only in the adenocarcinoma patients.ConclusionsOur analysis shows association of higher Enterobacteriaceae abundance with all types of gastric tumors. Therefore it could be potentially useful as a marker of gastric malignancies. Lower gut microbiota diversity might be indicative of poorly differentiated, invasive, advanced or aggressive tumors and could possibly be a prognostic marker for gastric tumors.

Gastric NET Subtypes: Do We Need An Additional One?

Depending on etiology, prognosis and malignant potential, recent S2k guideline differentiates gastric neuroendocrine tumors (gNET) in 4 types with different treatment implications.We report on a 55-year-old patient with the accidental finding of a 15 mm gNET. Apart from a prolonged use of proton pump inhibitors (PPI) for 20 years as a treatment for gastroesophageal reflux disease, there were no other associations or risk factors for gNETs. Formally, this patient would have been classified as a type III gNET, implicating gastric surgery. From a pathophysiological point of view, however, the assumed prolonged gastrin hypersecretion would have justified an assignment as a type I gNET. The gNET was resected by ESD, but histology showed an R1 situation. After cessation of PPIs, there is no recurrence so far. Besides, the initially documented numerous and large gland polyps showed an impressive regression only a few weeks after cessation of PPI.This case points to a probably underestimated gap in the present gNET classification. On the basis of present literature, the therapeutic dilemma of PPI-associated gNETs is discussed. A new assignment of PPI associated gNETs as type Ib could help to overcome this dilemma.

Case study: low grade dysplasia of intraductal papillary mucinous neoplasm progression to metastatic pancreatic adenocarcinoma despite complete pathologic resection

Presenter: Dena Steiner MD | Saint Elizabeth's Medical Center Background: Intraductal Papillary Mucinous Neoplasm (IPMN) management has been closely monitored due to the potentially high morbidity of unnecessary resection and the high mortality of delayed diagnosis of pancreatic cancer. Methods: This case study demonstrates a newly developed pancreatic cancer from the bed of a minimally symptomatic 4x3 cm low grade IPMN found on imaging with pancreatic dilation, mucin, a 15 x 10 mm mural nodule and multiple septations. Endoscopic ultrasound cytology was inconclusive for malignant cells, and a subsequent whipple procedure was revealing for mixed duct IPMN with low grade dysplasia, negative margins and 14 negative nodes. Results: One year later, he presented with bloating and subsequent imaging revealed metastatic cancer at the pancreatic bed and liver. He underwent chemotherapy and received palliative care following this diagnosis. Conclusion: Typically, low grade dysplasia in IPMNs subjugates them to a benign categorization, however this case challenges that determination. Malignant potential remains in these lesions with low grade dysplasia; and the mere presence of an IPMN may be a marker that all the patient’s pancreatic cells are at risk for malignant degeneration. Additionally, subcategorization into gastric, intestinal, pancreaticobiliary and oncocytic subtypes and determination of MUC13 expression may provide improved risk stratification.

Gastric Adenocarcinoma with Enteroblastic Differentiation: A Rare Find

Abstract Casestudy: Gastric adenocarcinoma with enteroblastic differentiation (GAED), also called clear cell gastric carcinoma, is a subtype of alpha-fetoprotein (AFP) producing adenocarcinoma. GAED is not a well-documented malignancy. Due to rarity, it is often skipped from the list of gastric adenocarcinoma subtypes. We report a case of Gastric adenocarcinoma with enteroblastic differentiation in a 69-year-old male, who had an endoscopy that revealed an ulcerated, circumferential, malignant-appearing mass at the distal esophagus. The patient then underwent proximal gastrectomy with distal esophagectomy. Received was a portion of the proximal stomach and distal esophagus. On gross examination, a 2.6 cm ulcerated mass was present at the gastroesophageal junction with white, friable, and focally necrotic cut surface. H&amp;E stained slides demonstrated a malignant tumor composed of cuboidal to columnar neoplastic cells with clear cytoplasm and prominent nucleoli. The neoplastic cells were arranged in tubular, solid, and trabecular growth patterns. There were also areas of admixed conventional moderately differentiated adenocarcinoma with overlying glandular dysplasia and focal intestinal metaplasia. Immunohistochemical stains demonstrated tumor positivity for CDX2 (strong) and AFP (focal). Neuroendocrine markers were negative within the tumor. In Conclusion, GAED is a rare malignancy with distinctive clinicopathologic features and associated aggressive behavior. Morphology and immunohistochemical stains are helpful in making the diagnosis of this rare malignancy.

A mixed-type intraductal papillary mucinous neoplasm of the pancreas with a histologic combination of gastric and pancreatobiliary subtypes in a 70-year-old woman: a case report

BackgroundIntraductal papillary mucinous neoplasms are rare papillary pancreatic neoplasms arising from major pancreatic ducts, characterized by duct dilation and mucin secretion. They comprise approximately 1% of all exocrine neoplasms and are classified according to their anatomical sites into main duct-type, branch duct-type, and mixed-type intraductal papillary mucinous neoplasms. Histological examination plays a crucial role in distinguishing and classifying intraductal papillary mucinous neoplasms into gastric, intestinal, pancreatobiliary, and oncocytic subtypes.Case presentationWe present the case of a 70-year-old Syrian woman who was admitted to our hospital due to an intermittent epigastric pain accompanied by diarrhea and weight loss with a recent diagnosis of diabetes mellitus. Following clinical, laboratory, and radiological examination, distal pancreatectomy involving the body and the tail of the pancreas was performed. Interestingly, histological examination of the resected specimens revealed the diagnosis of a mixed-type intraductal papillary mucinous neoplasm with a unique combination of gastric and pancreatobiliary subtypes.ConclusionTo the best of our knowledge, the combination of multiple histological subtypes of intraductal papillary mucinous neoplasms has been recorded in a few studies with reference to the challenging histological detection. Herein, we report a rare case with a significant histological combination, highlighting the difficulties in differential diagnosis due to the absence of ancillary techniques, with a brief review on diagnostic methods, histological characteristics and surgical recommendations.

RNF43 Mutations in IPMN Cases: A Potential Prognostic Factor.

An intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precursor lesion, and it often harbors mutations in KRAS, GNAS, and RNF43. To clarify the molecular profiles of IPMNs, we conducted mutation analysis of KRAS, GNAS, and RNF43 in 61 IPMN formalin-fixed, paraffin-embedded (FFPE) specimens. The mutation rates of codons 12, 13, and 61 in KRAS and codon 201 in GNAS were detected by Sanger sequencing. Next-generation sequencing was performed on RNF43, and the results were further verified by Sanger sequencing. We identified KRAS and GNAS mutations in 35 (57%) and 40 (66%) IPMN cases, respectively. GNAS mutations were significantly correlated with the morphologic subtype (P < 0.001) and were more prevalent in the intestinal subtype (93%) than in the gastric (55%) and pancreatobiliary subtypes (44%) but were absent in the oncocytic subtype. RNF43 mutations were found in 5 cases (8%), all of which occurred in high-grade dysplasia and invasive lesions (2/5 and 3/5). All 5 cases harboring RNF43 mutations also exhibited GNAS mutations. RNF43 mutations were associated with a worse prognosis in invasive IPMN patients (P = 0.002), while KRAS and GNAS mutations did not affect the prognosis of patients.