Intraductal Neoplasm Research Articles

Chromo-pancreatoscopy for preoperative evaluation of main duct intraductal pancreatic mucinous neoplasm

Chromo-pancreatoscopy for preoperative evaluation of main duct intraductal pancreatic mucinous neoplasm

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.

Selective inhibition of CDK9 in triple negative breast cancer

Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281–734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272–771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

Sialadenoma papilliferum-like intraductal papillary tumour: an emerging entity with intercalated duct differentiation showing MAPK pathway activation in both ductal and myoepithelial cells

Sialadenoma papilliferum-like intraductal papillary tumour (SP-IPT) is a recently described salivary gland tumour that shows identical morphology to sialadenoma papilliferum (SP) except for the lack of an exophytic papillary component. However, the immunohistochemical phenotypes and molecular profiles of SP-IPT remain unclear. This study aims to report new cases of SP-IPT and to determine its cellular differentiation and molecular basis. After histopathological review, four cases of SP-IPT were retrieved. Immunohistochemical staining was performed to analyse the expression patterns of cytokeratin 7 (CK7), p63, smooth muscle actin (SMA), vimentin, S100, mammaglobin, androgen receptor, SOX10, BRAF V600E-mutated protein, and phosphorylated ERK. Sanger sequencing was performed to determine the mutation status of the BRAF, KRAS, NRAS, and HRAS genes. All four cases affected the posterior mandible with a mean age of 62 years and a male-to-female ratio of 3:1. Histologically, all cases consisted of multiple tubular and cystic structures with varying sizes and shapes. The tubulocystic components were lined by a double or few-layered epithelium frequently showing a micropapillary pattern. The outer layer consisted of a rim of myoepithelial cells, which were CK7+/p63+/SMA+/vimentin+/S100+/SOX10+. The inner ductal cells were CK7+/S100+/SOX10+, consistent with intercalated duct differentiation. All cases harboured BRAF V600E mutations, but no other mutations were detected. The BRAF V600E-mutated protein and phosphorylated ERK were expressed in both ductal and myoepithelial cells. These findings demonstrate the immunohistochemical and molecular similarities between SP-IPT and SP and the role and extent of MAPK pathway activation in the pathogenesis of SP-IPT.

S2181 Multidisciplinary Approach to a Challenging Diagnosis of a Pancreatic Intraductal Neoplasm in the Ampulla of Vater

S2181 Multidisciplinary Approach to a Challenging Diagnosis of a Pancreatic Intraductal Neoplasm in the Ampulla of Vater

Breast MRI – The champion in the millimeter league: MIO breast MRI – The method of choice in women with dense breasts

We perform MRI of the breast as a first pass technique. We successfully established 10-minute-protocols (including T2 images) with a fixed dosage of 5 ml 1 M CM. A high spatial resolution of 526 × 526, better 672 × 672 or maximum (1.024 × 1.024, MIO MRI) is vital to achieve best results. We use fixation tools to avoid motion artifacts. Motion correction algorithms can, however, often eliminate such artifacts when they are present. In initial breast MRI exams, morphologic features are the most important criteria for lesion evaluation. If previous exams are available for comparison, the main criteria indicating a suspicious lesion are an increase in lesion size or the depiction of new lesions.High quality HR MRI of the breast is the method of choice in women with dense or extremely dense breasts in all cases (screening, assessment, follow up). In density type A or B, MRI can be helpful in defined constellations, e.g. when MX and US are limited or contraindicated.According to our experience, 95% or more of all carcinomas of the breast are detectable on MRI. The remaining 5% of MRI-occult lesions are intraductal tumors or very small invasive carcinomas depicted with mammography due to associated microcalcifications. MRI is, however, superior to all other imaging modalities in the detection of the clinically relevant DCIS (high risk DCIS, intermediate type).Consecutive MRI examinations in intervals of 12 to 24 months allow a reliable detection of invasive breast cancer with an average size of 7–8 mm. This corresponds to a rate of metastasis-free locoregional lymph nodes in >95% of cases. The rate of interval cancers is <2%. In conclusion, this strategy may increase the overall-lifetime survival of breast cancer patients to more than 95%. Inversely, mortality may be reduced to <5%.Taking these improvements in early breast cancer detection and survival that can be achieved through the implementation of QA HR MRI of the breast into account, it should be discussed to modify oncologic guidelines for the treatment of breast cancer.MRI is the best diagnostic tool we have and according to our experience, a first pass, quality-assured high-resolution breast MRI protocol provides best diagnostic results at minimal procedural effort.

Rare Solid Pancreatic Lesions on Cross-Sectional Imaging.

Several solid lesions can be found within the pancreas mainly arising from the exocrine and endocrine pancreatic tissue. Among all pancreatic malignancies, the most common subtype is pancreatic ductal adenocarcinoma (PDAC), to a point that pancreatic cancer and PDAC are used interchangeably. But, in addition to PDAC, and to the other most common and well-known solid lesions, either related to benign conditions, such as pancreatitis, or not so benign, such as pancreatic neuroendocrine neoplasms (pNENs), there are solid pancreatic lesions considered rare due to their low incidence. These lesions may originate from a cell line with a differentiation other than exocrine/endocrine, such as from the nerve sheath as for pancreatic schwannoma or from mesenchymal cells as for solitary fibrous tumour. These rare solid pancreatic lesions may show a behaviour that ranges in a benign to highly aggressive malignant spectrum. This review includes cases of an intrapancreatic accessory spleen, pancreatic tuberculosis, solid serous cystadenoma, solid pseudopapillary tumour, pancreatic schwannoma, purely intraductal neuroendocrine tumour, pancreatic fibrous solitary tumour, acinar cell carcinoma, undifferentiated carcinoma with osteoclastic-like giant cells, adenosquamous carcinoma, colloid carcinoma of the pancreas, primary leiomyosarcoma of the pancreas, primary and secondary pancreatic lymphoma and metastases within the pancreas. Therefore, it is important to determine the correct diagnosis to ensure optimal patient management. Because of their rarity, their existence is less well known and, when depicted, in most cases incidentally, the correct diagnosis remains challenging. However, there are some typical imaging features present on cross-sectional imaging modalities that, taken into account with the clinical and biological context, contribute substantially to achieve the correct diagnosis.

Intraductal neoplasms of the pancreatobiliary tract: navigating the alphabet.

Cancers of the pancreatobiliary tract are diseases with unfavourable prognoses. In the last couple of decades, two types of lesions have been described as precursors that precede pancreatobiliary cancers. These include incidental microscopic (flat) lesions known as pancreatic intra-epithelial neoplasia and biliary intra-epithelial neoplasia, and grossly visible, mass-forming lesions (tumoral intra-epithelial neoplasia) including intraductal papillary mucinous neoplasms, intraductal oncocytic papillary neoplasms, intraductal tubulopapillary neoplasms, intraductal papillary neoplasms of the bile duct and intracholecystic papillary neoplasms. Early detection and adequate treatment of these precursor lesions, especially the second group, have the potential to prevent pancreatobiliary cancer or at least improve its prognosis. In this review, we discuss their histopathology and recent updates on molecular profiling of these intraductal neoplasms of the pancreatobiliary tract.

A brief review of the WHO reporting system for pancreaticobiliary cytopathology.

The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer have developed an approach to standardized reporting of pancreaticobiliary cytopathology. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO System) revises the Papanicolaou Society of Cytopathology (PSC) System for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the 6 PSC categories with 7 categories: "Insufficient/Inadequate/Nondiagnostic"; "Benign/Negative for malignancy"; "Atypical"; "Pancreaticobiliary neoplasm, low risk/grade (PaN-low)"; "Pancreatic neoplasm, high risk/grade (PaN-High)"; "Suspicious for malignancy"; and "Malignant". In the PSC system, there is a single category for "Neoplastic" lesions that includes 2 groups, 1 for benign neoplasms and 1 named "Neoplastic-other", dominated by premalignant intraductal neoplasms primarily intraductal papillary mucinous neoplasms and low-grade malignant neoplasms (pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN). In the WHO System, benign neoplasms with virtually no risk of malignancy are included in the "Benign" category and low-grade malignancies (PanNET and SPN) are included in the "Malignant" category, as per the 5th edition of the WHO Classification of Digestive System Tumors, while the non-invasive pre-malignant lesions of the ducts are divided by the cytomorphological grade of the epithelium into PaN-low and PaN-high with distinctly different risks of malignancy. Within each category, key diagnostic cytopathologic features and the ancillary studies for diagnostic and prognostic evaluation, as well as the implications of diagnosis for patient care and management, are outlined. Reporting and diagnostic management options recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries.

Detection and endoscopic classification of intraductal neoplasms of the bile duct by peroral cholangioscopy with narrow-band imaging (with videos).

Indirect diagnostic modalities are unsatisfactory for detecting intraductal neoplasm of the bile duct (IN-B), which can be detected by peroral cholangioscopy (POC) with narrow-band imaging (NBI). We investigated the POC findings of IN-B and developed a feasible endoscopic classification system. Four hundred seventy-one patients who underwent direct POC from April 2008 to July 2020 were enrolled. Intraductal superficial lesions of the bile duct (ISL-Bs) were classified according to surface structure and microvascular pattern on POC with NBI and correlated to histologic findings after POC-guided forceps biopsy sampling (POC-FB) or surgery. The primary outcome was the detection rate of IN-Bs, and the secondary outcomes were the associations of POC findings with IN-B, technical success rates of POC and POC-FB, and adverse events. Direct POC was successful in 458 of 471 patients (97.2%). Among the patients, 131 (27.8%) exhibited ISL-Bs. The technical success rate of POC-FB was 94.7% (124/131). Among the 124 patients who underwent POC-FB, IN-B was revealed in 54 (43.5%), for a detection rate of 11.8% (54/458). Papillary lesions (P= .041), nodular lesions (P= .044), and irregularly or regularly dilated and tortuous vessels (P= .004 and P= .006, respectively) were POC findings associated with IN-B. The area under the receiver-operating characteristic curve of the novel classification system was .899. POC with NBI can be useful for the detection of IN-Bs. Our novel classification system based on both surface structure and microvascular pattern may allow differentiation of IN-B from ISL-Bs.

The Forms of the Lectin Tff2 Differ in the Murine Stomach and Pancreas: Indications for Different Molecular Functions.

The lectin TFF2 belongs to the trefoil factor family (TFF). This polypeptide is typically co-secreted with the mucin MUC6 from gastric mucous neck cells, antral gland cells, and duodenal Brunner glands. Here, TFF2 fulfills a protective function by forming a high-molecular-mass complex with the MUC6, physically stabilizing the mucus barrier. In pigs and mice, and slightly in humans, TFF2 is also synthesized in the pancreas. Here, we investigated the murine stomach, pancreas, and duodenum by fast protein liquid chromatography (FPLC) and proteomics and identified different forms of Tff2. In both the stomach and duodenum, the predominant form is a high-molecular-mass complex with Muc6, whereas, in the pancreas, only low-molecular-mass monomeric Tff2 was detectable. We also investigated the expression of Tff2 and other selected genes in the stomach, pancreas, and the proximal, medial, and distal duodenum (RT-PCR analysis). The absence of the Tff2/Muc6 complex in the pancreas is due to a lack of Muc6. Based on its known motogenic, anti-apoptotic, and anti-inflammatory effects, we propose a protective receptor-mediated function of monomeric Tff2 for the pancreatic ductal epithelium. This view is supported by a report that a loss of Tff2 promotes the formation of pancreatic intraductal mucinous neoplasms.

Successful Development of a Natural Language Processing Algorithm for Pancreatic Neoplasms and Associated Histologic Features.

Natural language processing (NLP) algorithms can interpret unstructured text for commonly used terms and phrases. Pancreatic pathologies are diverse and include benign and malignant entities with associated histologic features. Creating a pancreas NLP algorithm can aid in electronic health record coding as well as large database creation and curation. Text-based pancreatic anatomic and cytopathologic reports for pancreatic cancer, pancreatic ductal adenocarcinoma, neuroendocrine tumor, intraductal papillary neoplasm, tumor dysplasia, and suspicious findings were collected. This dataset was split 80/20 for model training and development. A separate set was held out for testing purposes. We trained using convolutional neural network to predict each heading. Over 14,000 reports were obtained from the Mass General Brigham Healthcare System electronic record. Of these, 1252 reports were used for algorithm development. Final accuracy and F1 scores relative to the test set ranged from 95% and 98% for each queried pathology. To understand the dependence of our results to training set size, we also generated learning curves. Scoring metrics improved as more reports were submitted for training; however, some queries had high index performance. Natural language processing algorithms can be used for pancreatic pathologies. Increased training volume, nonoverlapping terminology, and conserved text structure improve NLP algorithm performance.

High-Grade Ductal Carcinoma In Situ of the Breast With Regressive Changes: Radiological and Clinicopathological Findings.

Tumour regression is defined as continuity of changes leading to the elimination of a neoplastic population and is reflected as periductal fibrosis and intraductal tumour attenuation. The aim of this study was to describe the radiological and clinicopathological characteristics of high-grade breast ductal carcinoma in situ (DCIS) with regressive changes (RC). Thirty-two cases of high-grade DCIS with RC on biopsy specimens followed by excision were included. The mammographic, ultrasonographic (US), and magnetic resonance imaging (MRI) findings of cases were retrospectively reviewed according to the breast imaging reporting and data system (BI-RADS) lexicon. Clinical and histopathological findings [comedonecrosis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and Ki-67 proliferation index] were recorded. The rate of upgrade to invasive cancer after surgical excision and lymph node involvement were evaluated. The most common mammographic finding was microcalcifications alone (68.8%). The most frequently seen findings on US were microcalcifications only (21.9%), followed by microcalcifications and hypoechoic area (18.7%). On MRI, most lesions presented as clumped non-mass enhancement with segmental distribution. ER/PR negativity (53.1%, 65.6%), HER2 positivity (56.3%) and high Ki-67 (62.5%), which are known to be associated with more aggressive behavior, were found to be proportionally higher. The rate of upgrade to invasive cancer was 21.8%. DCIS with RC lesions present most often as microcalcifications alone on both mammography and US. MRI features are not distinguishable from those of other DCIS lesions. DCIS with RC lesions show biomarker status reflecting more aggressive behavior and high upgrade rate to invasive cancer.

Nipple Temperatures in Breast Thermography

Objective: Since the advent of microbolometer infrared imagers that allow qualitative and quantitative nipple temperature assessment, peer-reviewed guidelines have stated that normal differential nipple temperatures should not exceed 1.0 °C. This study is designed to examine the validity of this and other nipple temperature measurements in a clinical breast thermography population. Methods: 211 women between 27 and 83 years of age underwent standard breast thermography. Images of 422 breasts were taken and analyzed. Average area temperatures were obtained for both the breasts and nipples. Besides analyzing the combined data from all subjects, three subsets of data with different Thermobiological (TH) evaluations and a subset of women with bilateral breast implants were analyzed. Results: Absolute breast temperature declined about 1°C from age 27 to 83. Nipple temperature was unaffected by age. A strong correlation was found between ipsilateral breast and nipple temperatures. Nipple temperatures were cooler than the breast in 93.8% of 422 samples. Nipple temperature increased relative to the breast temperature as the TH evaluation increased. Average right breast and nipple temperatures were warmer than the Left in all data sets. Nipple temperature difference tends to rise faster than breast temperature difference. As the TH evaluation increased, differential breast temperatures remained constant while nipple differentials increased. Women with breast implants were found to have the least variation in breast and nipple temperatures. Conclusions: Normal nipple temperature is less than breast temperature by an average of 1.1°C. A cutoff value for maximum nipple temperature difference is graphically confirmed to be 1.0 °C. Maximum breast temperature difference cutoff is 0.5°C, and a vector sum of these differences should be less than 1.5°C. Nipple temperatures are controlled by sympathetic neural tone and by local nitric oxide concentration. Lactiferous duct infection and intraductal tumors (DCIS) increase intraductal NO, which is directed up the duct to the nipple. Increased nipple temperature may signal the presence of breast pathology.

Tumoral Intraductal Neoplasms of the Bile Ducts Comprise Morphologically and Genetically Distinct Entities.

Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. To investigate their morphologic, immunohistochemical, and molecular features. Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.

Endoscopic ultrasound-guided intervention for inaccessible papilla in advanced malignant hilar biliary obstruction.

Advanced malignant hilar biliary obstruction (MHBO) with inaccessible papilla poses a significant challenge to endoscopists, as drainage of multiple liver segments may be warranted. Transpapillary drainage may not be feasible in patients with surgically altered anatomy, duodenal stenosis, prior duodenal self-expanding metal stent, and after initial transpapillary drainage, but require re-intervention for draining separated liver segments. Endoscopic ultrasound-guided biliary drainage (EUS-BD) and percutaneous trans-hepatic biliary drainage are the feasible options in this scenario. The major advantages of EUS-BD over percutaneous trans-hepatic biliary drainage include a reduction in patient discomfort and internal drainage away from the tumor, thus reducing the possibility of tissue or tumor ingrowth. With innovations, EUS-BD is helpful not only for bilateral communicating MHBO but also for non-communicating systems with bridging hilar stents or isolated right intra-hepatic duct drainage by hepatico-duodenostomy. EUS-guided multi-stent drainage with specially designed cannulas and guidewires has become a reality. A combined approach with endoscopic retrograde cholangiopancreatography for re-intervention, interventional radiology, and intraductal tumor ablative therapies has been reported. Stent migration and bile leakage can be minimized with proper stent selection and technique, and stent blocks can be managed with EUS-guided interventions in a majority of cases. Future comparative studies are required to establish the role of EUS-guided interventions in MHBO as rescue or primary therapy.

Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma

Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz–Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker.

Abstract A081: Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms

Abstract Objective: Morphological subtyping of intraductal papillary mucinous neoplasms of the pancreas (IPMNs) into pancreatobiliary-type, intestinal-type, or gastric-type is a prognostic factor, however, molecular foundations explaining the difference of clinical behaviors are unknown. Our research aimed to elucidate the molecular phenotypes associated with subtypes of IPMNs and establish a risk stratification model. Design: In 171 IPMNs with high-grade dysplasia (HGD) and invasive carcinoma, we analyzed protein expressions of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry, and mutations and copy number variations of KRAS and GNAS by droplet digital PCR, and analyzed the association with clinicopathological factors. Results: In HGD components of IPMNs of pancreatobiliary- (n=66), intestinal- (n=70), and gastric-type (n=35), alterations were detected respectively as follows: KRAS mutation; 98%, 62%, and 83% (P&amp;lt;0.05), GNAS mutation; 11%, 82%, and 51% (P&amp;lt;0.05), p53; 59%, 33%, and 20% (P&amp;lt;0.05), SMAD4; 67%, 1%, 37% (P&amp;lt;0.05), STK11; 43%, 3%, and 6% (P&amp;lt;0.05), β-catenin; 48%, 68%, and 23% (P&amp;lt;0.05), and p16; 65%, 52%, and 40% (P=0.105). Aberrations of 4 driver genes, p16, p53, SMAD4, and STK11, were succeeded from components of low-grade dysplasia to invasive carcinoma and associated with the risk of invasion of intraductal neoplasms and the patients’ outcomes. The combinatorial system by the number of accumulated gene alterations well stratified the risk of invasion (0–1 vs 2; odds ratio (OR) 4.62, 0–1 vs 3–4; OR 12.90) and patients’ outcome (0–1 vs 2; hazard ratio (HR) 4.01, 2 vs 3–4; HR 3.98, 0–1 vs 3–4; HR 15.99 in disease-free survival, 0–1 vs 2; HR 6.62, 2 vs 3–4; HR 4.43, 0–1 vs 3–4; HR 29.32 in overall survival). Moreover, GNAS amplification was an independent risk factor of invasion (OR 7.79) and showed poor prognosis (overall survival, log-rank P&amp;lt;0.05) in intestinal-type IPMNs, while sole GNAS activating mutation was an independent low risk factor for invasion (OR 0.33). KRAS amplification might be a poor prognostic factor in pancreatobiliary-type IPMNs (HR 2.7, P=0.07). Conclusion: The molecular patterns involving the malignant progression are different among epithelial subtypes of IPMNs. The molecular phenotypes of combinatorial genomic alterations of tumor suppressor genes with signature of KRAS and GNAS of intraductal components may stratify the risk of invasion and survival in IPMN patients. Molecular phenotyping using liquid biopsy of pancreatic juice during the surveillance might be additional value of decision making for operative timing in IPMNs showing equivocal radiological findings. Citation Format: Yuko Omori, Yusuke Ono, Takashi Kokumai, Fumiko Date, Ryota Higuchi, Goro Honda, Yusuke Mizukami, Takanori Morikawa, Michiaki Unno, Toru Furukawa. Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A081.

Abstract A035: Profiling of circulating autoreactive antibodies in some 1200 patients with pancreatic ductal adenocarcinoma and progressive precursor lesions

Abstract Tumor-associated autoreactive antibodies could represent a moderately sensitive but highly specific type of biomarker. While autoantibodies in the blood of patients with pancreatic cancer have been reported, the consensus among studies is low and data validation is lacking. We profiled the abundance of circulating autoantibodies in patients with pancreatic ductal adenocarcinoma (PDAC) in a multi-step approach. For this purpose, microarrays with in situ expressed proteins were produced that contained 3060 non-mutated human proteins; one emphasis was on cell surface proteins. The microarrays were utilized for autoantibody screening of sera collected from patients of PDAC stages I, IIA, IIB/III and IV. In addition, samples were studied that represented the different grades of the precursor lesion intraductal pupillary mucinous neoplasm (IPMN) – low-grade, high-grade dysplasia and IPMN with associated carcinoma. Third, sera from patients diseased with the PDAC risk factor chronic pancreatitis (CP) as well as healthy donors served as control groups. The analysis revealed a significant increase in the overall proportion of immunoreactive proteins in late grades of IPMN and stages of PDAC; within each group, some sera displayed higher reactivity than others. The screening phase led to the identification of about 100 proteins, which showed a relatively high immunoreactivity associated with PDAC in comparison to an age- and sex-matched healthy control group. The characteristics of PDAC-associated autoantibodies were confirmed for the 100 proteins by analyzing sera from a total of 1200 PDAC, IPMN and CP patients as well as healthy donors. The patient groups were age- and sex-matched among each other. This confirmation phase validated the PDAC-related immunoreactivity of 17 proteins, showing high specificity of samples from PDAC patients in comparison to the healthy control group but low sensitivity of less than 10%. The clinically defined PDAC stages displayed different autoantibody profiles. However, no stage-related autoantibodies could be identified. Further, these PDAC-related antigens were also immunoreactive in smaller proportions of CP and IPMN patients, demonstrating the biological relation between PDAC and its precursors CP and IPMN. The majority of the other antigens showed a high immunoreactivity without correlation of autoantibody abundance and PDAC diagnosis, highlighting the importance of validation in large cohorts. The presence of autoantibodies specific for the 17 identified PDAC-related proteins is currently technically cross-validated by Luminex multiplex serology. In conclusion, the study has identified novel PDAC-related autoantibodies towards non-modified human proteins. While the specificity of some detected autoantibodies was high, the low sensitivity and the immunoreactivity of related precursor lesions make the definition of a broad applicable biomarker panel unlikely or too complex. However, the antigens that are specific for PDAC indicate target molecules, which could offer new therapeutic options in a personalized approach. Citation Format: Henning Boekhoff, Laura Hendricks, Elena Cairo, Andrea Bauer, Mari Hambardzumyan, Markus W. Büchler, Silvia Calderazzo, Vivienn Weru, Anette Kopp-Schneider, Hermann Brenner, Thilo Hackert, Oliver Strobel, Tim Waterboer, Nathalia Giese, Joerg D. Hoheisel. Profiling of circulating autoreactive antibodies in some 1200 patients with pancreatic ductal adenocarcinoma and progressive precursor lesions [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A035.

Pathologies of Precursor Lesions of Biliary Tract Carcinoma.

Carcinomas and precursor lesions of the biliary tract belong to a spectrum of pancreatobiliary neoplasms that share common histology and cell lineages. Over the past two decades, preinvasive precursors to biliary tract carcinomas (BTCs) have been identified such as high-grade biliary intraepithelial neoplasm (high-grade BilIN), intraductal papillary neoplasm of bile duct (IPNB) and intracholecystic papillary neoplasm of the gallbladder (ICPN). While a majority of these precursors may arise from the biliary tract mucosa, some originate from the peribiliary glands and Rokitansky-Aschoff sinuses in the walls of the biliary tract. High-grade BilIN is a microscopically identifiable intraepithelial neoplasm of the biliary tract, whereas IPNB and ICPN are grossly visible intraductal or intraluminal preinvasive neoplasms in the bile duct and gallbladder, respectively. These neoplasms show characteristic histologic features according to four cell lineages and two-tiered grading, and show intraepithelial spreading to the surrounding mucosa and involve non-neoplastic glands in the walls of the biliary tract. These precursors are not infrequently associated with stromal invasion, and high-grade BilIN, in particular, are frequently identified in the surrounding mucosa of BTCs. Taken together, it seems likely that progression from these precursors to invasive carcinoma is a major process in biliary carcinogenesis.