Toru Furukawa

Background: High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is a non-invasive precursor of pancreatic ductal adenocarcinoma (PDAC) that is notoriously difficult to detect preoperatively because it lacks a discrete mass. Comprehensive imaging–pathology correlation studies focusing exclusively on HG-PanIN remain limited. Methods: We retrospectively analyzed 50 patients with surgically resected, pathologically confirmed HG-PanIN without invasive carcinoma from 11 institutions participating in the Japan Study Group on Early Detection of Pancreatic Cancer (JEDPAC). Central pathological review classified lesions by ductal involvement pattern: Group A (main pancreatic duct [MPD] only), Group B (MPD plus branch ducts), and Group C (branch ducts only). Imaging findings on CT, MRI/MRCP, and endoscopic ultrasound (EUS) were correlated with pathological intraductal spread length. Diagnostic sensitivity of serial pancreatic-juice aspiration cytologic examination (SPACE) and EUS-guided fine-needle aspiration (EUS-FNA) was compared. Results: The median follow-up was 63 months. Five-year overall survival was 92%, with remnant pancreas recurrence observed in 12%. MPD stenosis was consistently observed in MPD-involved lesions, even with minimal intraductal spread. Periductal hypoechoic areas and focal pancreatic atrophy increased with greater intraductal extension. Group C lesions frequently presented as cystic changes without MPD stenosis. SPACE showed a higher diagnostic yield than EUS-FNA in this cohort (77.1% vs. 25.0%), although this comparison was limited by the small number of EUS-FNA cases. Conclusions: HG-PanIN exhibits distinct imaging patterns that correlate closely with ductal involvement and pathological extent. Localized MPD stenosis is the earliest imaging hallmark, and SPACE may be a useful diagnostic tool for non–mass-forming lesions. Integration of imaging, cytology, and pathology is essential for early detection of pancreatic cancer.

Secretory carcinomas (SCs) of the salivary gland have recently been recognized as low-grade, malignant tumors. Before this designation, most SCs were diagnosed as variants of acinic cell carcinomas (AciCCs). SCs harbor the t(12;15)(p13;q25) translocation that generates an oncogenic fusion gene, ETS variant transcription factor 6/Neurotrophic tyrosine receptor kinase(ETV6::NTRK3). However, detecting fusion genes in a clinical setting is time-consuming and costly. In this study, we examined 31 cases previously diagnosed as AciCC and SC using pathological analyses with detection of fusion genes using ETV6 break-apart fluorescence in-situ hybridization and reverse transcription-polymerase chain reaction. After re-analysis, we found that these 31 cases actually comprised 21 SCs and 10 AciCCs. We examined the diagnostic utility of immunohistochemistry by comparing results with the fusion gene, Pan-Trk, which despite having recently been reported as effective for diagnosis of SC, was not universally accurate. However, combining mammaglobin and S-100 could be particularly useful in diagnosing SC. This practical method will contribute to accurate diagnosis of SCs, while saving time in daily clinical practice.

Background: Germline mutations in BRCA1/2 are known to cause hereditary tumors in the breast, ovary, and other organs. With the widespread adoption of comprehensive diagnostics, including comprehensive genomic profiling (CGP) tests for solid tumors, many patients with BRCA1/2 variants have been identified.Methods: In this study, we extracted and analyzed cases of BRCA1/2 variants that were presumed to be germline, which were repeatedly detected using the CGP test for solid tumors in northeastern Japan. The frequencies of BRCA1/2 variants in regional areas were compared with those of healthy individuals or nationwide cancer cohorts to investigate regional distribution.Results: Our findings revealed regional disparities in BRCA1/2 pathogenic germline variants, while variants of unknown significance (VUS) showed no such differences. The regional distribution of BRCA1 and BRCA2 variants showed distinct patterns: pathogenic variants of BRCA1 exhibited regional differences and were less prevalent compared to VUS, whereas BRCA2 variants, including both pathogenic variants and VUS, did not exhibit such clear regional localization. This discrepancy in regional distribution between BRCA1 and BRCA2 variants could be attributed to factors such as the diversity of the genome, gender differences, and cancer types.Conclusions: These results highlight the importance of considering regional differences in comparative cohort studies, particularly in assessing the differential extension of mutations in pathogenic changes and VUS. Moreover, a presumption of pathogenicity variants would need to be discussed at the regional level.

Objectives: Treating pancreatic ductal adenocarcinoma (PDAC) is a major clinical challenge, owing to its poor prognosis. Understanding the underlying molecular interactions may be crucial in determining PDAC intractability. We elucidated the combinatory role of SMAD family member 4 (SMAD4) and runt-related transcription factor 3 (RUNX3) in PDAC. Methods: Formalin-fixed and paraffin-embedded tissues were obtained from 101 patients who underwent surgical resection of PDAC. SMAD4 and RUNX3 expression in the tissues was evaluated using immunohistochemistry. SMAD4 and KRAS mutations were evaluated using Sanger sequencing. SMAD4 copy number variations were evaluated using quantitative real-time polymerase chain reaction. These molecular characteristics were compared with patients' clinicopathological features. Results: Retained SMAD4 expression in PDAC tissues was associated with higher tumor, node, metastasis (TNM) stage, and metastatic recurrence. Defective RUNX3 expression was associated with higher TNM stages. Further analysis to determine significance of retained SMAD4 indicated that all these cases had defective RUNX3 expression; therefore, the combined expression status of retained SMAD4 and defective RUNX3 expression in tissues was determined to be associated with higher TNM stage and metastatic recurrence than defective SMAD4 expression with defective or retained RUNX3 expression. Survival analysis showed that patients with tumors with retained SMAD4 and defective RUNX3 expression had relatively worse overall survival rates. KRAS mutations were not associated with SMAD4/RUNX3 expression or overall survival. Conclusions: Despite inherent limitations of this retrospective study and small sample size, our findings highlight the potential combined role of SMAD4 and RUNX3 in node metastasis and metastatic recurrence in patients with resected PDAC.

Peritoneal washing cytology (CY) in patients with pancreatic cancer is mainly used for staging; however, it may also be used to evaluate the intraperitoneal status to predict a more accurate prognosis. Here, we investigated the potential of deep learning of CY specimen images for predicting the 1-year prognosis of pancreatic cancer in CY-positive patients. CY specimens from 88 patients with prognostic information were retrospectively analyzed. CY specimens scanned by the whole slide imaging device were segmented and subjected to deep learning with a Vision Transformer (ViT) and a Convolutional Neural Network (CNN). The results indicated that ViT and CNN predicted the 1-year prognosis from scanned images with accuracies of 0.8056 and 0.8009 in the area under the curve of the receiver operating characteristic curves, respectively. Patients predicted to survive 1 year or more by ViT showed significantly longer survivals by Kaplan-Meier analyses. The cell nuclei found to have a negative prognostic impact by ViT appeared to be neutrophils. Our results indicate that AI-mediated analysis of CY specimens can successfully predict the 1-year prognosis of patients with pancreatic cancer positive for CY. Intraperitoneal neutrophils may be a novel prognostic marker and therapeutic target for CY-positive patients with pancreatic cancer.

In 2023, the Japan Pancreas Society (JPS) published the new eighth edition of the Japanese classification of pancreatic carcinoma. We present here an excerpted version in English, based on the latest edition. The major changes in this revision are as follows: In the eighth edition of the Union for International Cancer Control (UICC), the T category was changed to be based on tumor size; however, the eighth edition of the Japanese classification retains the previous T category based on local invasion factors. Lymph nodes have been renamed, and regional lymph nodes have been defined by location. Peritoneal cytology, which was not previously included in distant metastasis (M), has now been included in the M category. Moreover, significant additions have been made regarding the pathological diagnosis of endoscopic ultrasound‐guided fine‐needle aspiration biopsy (EUS‐FNAB) and criteria for histological assessment of the effects after chemotherapy and radiation therapy. Although this classification is aimed at carcinoma originating in the pancreas, not in the bile duct or duodenum, if the differentiation of the primary organ is difficult, this classification should be applied. It is also desirable to describe tumors other than carcinoma and metastatic tumors to the pancreas in accordance with this classification.

Objective: To clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. Background: Molecular mechanisms of the development of remnant PCs after 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. Clinicopathologic 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 through 3 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. Conclusions: Molecular profiling uncovered 3 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.

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.

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.