Pancreas/Biliary, in full.

Evaluate suspected pancreatic adenocarcinoma with a dedicated pancreatic-protocol (multiphasic, contrast-enhanced) CT of the abdomen as the preferred imaging for diagnosis and staging (MRI/MRCP is an acceptable alternative); PET/CT may be added after, never as a substitute for, protocol CT/MRI in higher-risk situations. Obtain tissue confirmation, preferably by EUS-guided FNA/FNB with core biopsy where feasible; biopsy is generally required before neoadjuvant or palliative therapy, whereas patients with clearly resectable disease may proceed to surgery without preoperative biopsy. Measure baseline CA 19-9 (interpret after biliary decompression / with normal bilirubin; it can be falsely low in Lewis-antigen-negative patients and falsely elevated with cholestasis). Offer GERMLINE testing for inherited susceptibility to EVERY patient with confirmed pancreatic adenocarcinoma regardless of family history, using a comprehensive multi-gene panel; separately, for patients with locally advanced or metastatic disease who are candidates for anti-cancer therapy, obtain TUMOR/SOMATIC molecular profiling (broad NGS; RNA-based assays improve fusion detection; cell-free/liquid biopsy if tissue is insufficient). Assign resectability, resectable, borderline resectable, locally advanced (unresectable), or metastatic, by multidisciplinary review, ideally at a high-volume center. RESECTABLE disease: upfront resection (pancreaticoduodenectomy for head/uncinate; distal pancreatectomy ± splenectomy for body/tail) followed by adjuvant therapy, or neoadjuvant therapy in selected high-risk patients; preferred adjuvant regimen is modified FOLFIRINOX in patients able to tolerate it, ideally begun within 12 weeks of surgery, for a total of ~6 months of perioperative systemic therapy. BORDERLINE RESECTABLE and LOCALLY ADVANCED disease: neoadjuvant systemic therapy, with or without subsequent chemoradiation/RT, then restaging and reassessment for resection. METASTATIC disease by performance status: good PS (ECOG 0-1, adequate organ function), first-line FOLFIRINOX/modified FOLFIRINOX, NALIRIFOX, or gemcitabine + nab-paclitaxel, with clinical trial preferred; after ~4-6 months without progression, transition to a maintenance strategy (including olaparib for germline BRCA1/2 carriers who have NOT progressed on first-line platinum-based therapy), a clinical trial, or a treatment break; intermediate PS (ECOG 2), clinical trial preferred, otherwise less-intensive first-line therapy (preferred gemcitabine + nab-paclitaxel [category 1], or single-agent gemcitabine or capecitabine, or FOLFOX/FOLFIRI/CapeOx), since the intensive triplets (FOLFIRINOX/modified FOLFIRINOX and NALIRIFOX) are limited to ECOG 0-1 and are generally not appropriate at ECOG 2, with the same maintenance-versus-progression reassessment applied after ~4-6 months without progression; poor PS (ECOG 3-4), palliative/best supportive care, with single-agent chemotherapy or a biomarker-directed agent only if clinically appropriate. Treat by molecular target wherever an actionable alteration is present, across lines: pembrolizumab (or dostarlimab) for MSI-H/dMMR and pembrolizumab for TMB-H, olaparib for germline BRCA1/2 (maintenance after platinum), larotrectinib/entrectinib for NTRK fusions, selpercatinib for RET fusions, dabrafenib + trametinib for BRAF V600E, erdafitinib for FGFR2 alterations, fam-trastuzumab deruxtecan for HER2-positive disease, zenocutuzumab for NRG1 fusion-positive disease, and (in recent NCCN versions) KRAS G12C inhibitors (adagrasib/sotorasib), several of these after prior systemic therapy. Integrate supportive care throughout: relieve obstructive jaundice with an endoscopic self-expanding metal stent in non-operative or neoadjuvant pathways, but do NOT perform routine preoperative biliary drainage before planned upfront resection; treat exocrine insufficiency with pancreatic enzyme replacement titrated to symptoms (common starting dose ~40,000-50,000 units of lipase with main meals, roughly half with snacks, increased as needed); manage refractory pain with celiac plexus neurolysis or palliative RT; relieve gastric outlet obstruction with surgical or EUS-guided gastrojejunostomy (or enteral stenting); and provide VTE prophylaxis, nutritional support, and early palliative care.

Risk-stratify suspected choledocholithiasis (high >50%, intermediate 10-50%, low <10% probability). HIGH-risk criteria, any of which should directly prompt ERCP: (1) CBD stone on ultrasound or cross-sectional imaging; (2) ascending cholangitis; (3) total bilirubin >4 mg/dL AND dilated CBD (>6 mm in adults with gallbladder in situ, >8 mm after cholecystectomy). Gallstone pancreatitis was deliberately REMOVED as a high-risk criterion in the 2019 revision. INTERMEDIATE risk (abnormal liver biochemical tests, age >55 y, or bile-duct dilation on imaging): the panel suggests confirmation with either EUS or MRCP (conditional recommendation, low-quality evidence; choice by patient preference, local expertise, availability), laparoscopic intraoperative cholangiography (IOC) or intraoperative US are equally sanctioned alternatives. LOW risk: cholecystectomy with or without IOC/intraoperative US if indicated for symptomatic cholelithiasis; no ERCP and no mandatory advanced biliary imaging. In gallstone pancreatitis WITHOUT cholangitis or biliary obstruction/choledocholithiasis, the panel recommends AGAINST urgent (<48 h) ERCP (strong recommendation, low-quality evidence). Same-admission cholecystectomy is recommended for patients with MILD gallstone pancreatitis (consensus, PONCHO-based); ERCP with prophylactic sphincterotomy should not be used as an alternative to cholecystectomy unless surgery is absolutely contraindicated (e.g., recurrent pancreatitis in end-stage liver disease). For large bile-duct stones, the panel suggests endoscopic sphincterotomy followed by large-balloon dilation (ES-LBD) rather than sphincterotomy alone (conditional, moderate); for large AND difficult stones, it suggests intraductal therapy (cholangioscopy-guided EHL or laser lithotripsy) or conventional therapy with papillary dilation, chosen by local expertise, cost, and patient/physician preference (conditional, very low). Timing versus cholecystectomy: pre- or postoperative ERCP or laparoscopic bile-duct clearance for patients at high risk or with positive IOC, depending on local surgical and endoscopic expertise (consensus).

Stage cholangiocarcinoma with multiphasic MRI/MRCP plus CT chest/abdomen/pelvis, obtain tissue via ERCP brush cytology with FISH, cholangioscopy-directed biopsy, or EUS-FNA (avoiding primary perihilar tumor sampling if liver transplant is being considered due to theoretical seeding risk), and manage through a multidisciplinary tumor board with treatment stratified by tumor location: resect (anatomic hepatectomy for intrahepatic, hemihepatectomy with bile duct resection for perihilar, Whipple for distal) with adjuvant capecitabine (category 1, per BILCAP) when resectable. For unresectable or metastatic disease, first-line systemic therapy is gemcitabine plus cisplatin combined with a PD-L1/PD-1 checkpoint inhibitor, either durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966), both listed as category 1 preferred options by NCCN; comprehensive molecular/genomic profiling is recommended for all unresectable/metastatic candidates for systemic therapy to identify actionable targets (e.g., FGFR2 fusions, IDH1 mutations, HER2 amplification) for later-line therapy. Selected unresectable early-stage perihilar tumors may undergo neoadjuvant chemoradiation and liver transplant per the Mayo Clinic protocol at experienced centers, and jaundice or cholangitis is managed with biliary drainage (ERCP preferred over PTC).

The CAPS Consortium recommends pancreatic surveillance for selected high-risk individuals to detect stage I (T1N0M0, margin-negative resectable) pancreatic cancer and high-grade precursors (PanIN-3, IPMN with high-grade dysplasia); it should ideally be performed in a research setting by a multidisciplinary team at a center with appropriate expertise. Candidate groups and their affected-relative requirements: Peutz-Jeghers/STK11 carriers regardless of family history; CDKN2A carriers regardless of family history (surveillance regardless of family history reached 77% agreement, still meeting the guideline's ≥75% consensus threshold as a Grade 1 'definitely do it' recommendation, while surveillance in those with at least one affected first-degree relative reached stronger 99% agreement); BRCA2 carriers with at least one affected FDR or at least two affected relatives of any degree; ATM, PALB2, and Lynch (MLH1/MSH2/MSH6) carriers only if at least one affected FDR; BRCA1 with an affected FDR did NOT reach consensus; hereditary pancreatitis was an area of disagreement (no consensus on whether or how to surveil); and familial pancreatic cancer kindreds, an individual with at least one affected FDR who in turn has an affected FDR, qualify on pedigree alone without an identified germline variant. Germline testing and genetic counseling should be considered for those eligible for surveillance but are not an absolute prerequisite. Start ages (exact age often did not reach consensus): CDKN2A at age 40; Peutz-Jeghers at least by age 40, or 10 years younger than the youngest affected relative; hereditary pancreatitis/PRSS1 at age 40 or 20 years after the first attack; BRCA2/ATM/PALB2/BRCA1/Lynch carriers at age 45 or 50, or 10 years younger than the youngest affected relative; familial pancreatic cancer kindreds at age 50 or 55, or 10 years younger than the youngest affected relative (experts split between 50 and 55). New-onset diabetes in a high-risk individual should trigger screening regardless of age. Modalities: both baseline and follow-up surveillance use EUS and MRI/MRCP, alternated (consensus that both are used, but NO consensus on if or how to alternate them); CT is reserved for individuals who cannot undergo MRI/EUS or when a solid lesion is detected; CA19-9 is an additional test only when imaging shows worrisome features; routine fasting glucose and/or HbA1c testing is advised. Interval: in the absence of pancreatic abnormalities, or with only low-risk findings such as pancreatic lobulation, cysts without worrisome features, or a <1 cm non-functioning neuroendocrine tumor, continue 12-monthly imaging. Concerning findings: a newly detected solid lesion of uncertain significance should be re-imaged at 3 months (3-6 months for CDKN2A carriers); EUS-FNA is indicated for solid lesions ≥5 mm, cystic lesions with worrisome features (mural nodule, solid component, duct dilation), or a main-pancreatic-duct stricture without a mass. Surgical resection, performed at a specialty center as an oncologic/radical resection, is indicated for a solid lesion (≥5 mm; resection regardless of size did not reach consensus), or an IPMN with a mural nodule, an enhancing solid component, symptoms (pancreatitis/jaundice/pain), or a main pancreatic duct ≥10 mm. Surveillance of average-risk individuals is not recommended.