Pancreatic cancer is a malignant neoplasm of the pancreas. About 90% of cases are pancreatic ductal adenocarcinoma (PDAC). Pancreatic neuroendocrine neoplasms form a separate group with their own grading and staging.^[1][2] Pancreatic cancer is classified along three axes: histologic type under the WHO classification of digestive system tumors (5th edition, 2019, with 2026 refinements), grade, and anatomic extent under the AJCC 8th-edition TNM system, which has separate schemes for exocrine adenocarcinoma and neuroendocrine tumors. Key changes from older teaching include a two-tier (low-grade/high-grade) system for pancreatic intraepithelial neoplasia (PanIN) and Ki-67/mitotic grading of neuroendocrine tumors that recognizes a well-differentiated G3 category.^[2][3]

Pancreatic cancer became a surgical disease in the late 19th century. Pancreatoduodenectomy, developed by Kausch (1912) and popularized by Whipple (1935–1941), became a survivable operation. Centralization in high-volume centers later lowered operative mortality from roughly 25–33% to about 1–2%. With multimodal therapy, 5-year survival after resection is now about 20–30%, although only about 15–20% of patients have resectable disease at diagnosis.^[4][5][6]

PDAC develops as precursor lesions acquire an activating KRAS mutation (about 85–95% of tumors) and inactivation of the tumor suppressor genes CDKN2A, TP53, and SMAD4.^[7][8] The EGFR, Akt, NF-kB, and Hedgehog pathways are commonly involved, and altered TGF-beta signaling produces the characteristic dense desmoplastic stroma. Tumors extend locally into the peripancreatic vessels, nerves, duodenum, and stomach, and spread to regional lymph nodes. About 5–10% of unselected patients carry a pathogenic germline variant, most often in DNA damage repair genes, rising to about 30% in early-onset disease. At least half of carriers have no suggestive family history, so universal germline testing is recommended for every patient with PDAC.^[8][9][10]

Pancreatic cancer must be differentiated from other pancreatic diseases such as chronic and autoimmune pancreatitis, pancreatic pseudocyst, and pancreatic neuroendocrine tumors. It must also be differentiated from biliary and duodenal disease, including choledocholithiasis, cholelithiasis, choledochal cysts, cholangiocarcinoma, bile duct strictures, and ampullary cancer, as well as from metastasis from other sites and abdominal aortic aneurysms.

Pancreatic cancer is the third leading cause of cancer death in the United States and is projected to become the second by about 2030. U.S. incidence and mortality are nearly equal (18.7 and 15.8 per 100,000 in 2021).^[9][11] Incidence rises steeply after age 50 and is higher in men and in non-Hispanic Black individuals. Early-onset disease is increasing in the U.S., mainly among women.^[9][12] The main acquired risk factors are cigarette smoking (the leading modifiable cause, about 20% of cases), obesity, long-standing type 2 diabetes, heavy alcohol use, and chronic pancreatitis. New-onset diabetes mellitus in older adults often reflects occult PDAC rather than causing it.^[1][13]

The USPSTF recommends against screening average-risk adults (Grade D). High-risk individuals, meaning carriers of a pathogenic or likely pathogenic germline variant or people with a qualifying family history, should have annual MRI/MRCP and/or endoscopic ultrasound at experienced high-volume centers.^[14][15][16] The rationale is stage: 5-year survival approaches about 80% for stage IA disease but is 3–16% at regional or distant stage.^[17]

PDAC develops over many years at the molecular level but progresses rapidly once clinically apparent.^[7] Major complications include biliary obstruction, gastric outlet/duodenal obstruction, cancer-related pain, exocrine insufficiency, cachexia, and venous thromboembolism. Overall 5-year relative survival is about 12–13%. It is about 46% for localized disease and about 3% for distant disease.^[18][8]

Common symptoms include mid-epigastric pain, jaundice, unexplained weight loss, dark urine, and light-colored or greasy stools. On examination, patients may be cachectic, with a palpable abdominal mass, epigastric tenderness radiating to the back, and signs of metastasis such as Virchow’s node, Sister Mary Joseph’s node, and Blumer’s shelf. Laboratory findings are nonspecific and include cholestatic liver function tests, mild anemia, and elevated CA 19-9. Pancreas-protocol multidetector CT is the primary imaging modality. MRI is used when CT is equivocal and to characterize cystic lesions, and EUS detects tumors smaller than 2 cm and aids local staging. EUS-guided fine-needle aspiration is the best modality for tissue diagnosis. Staging uses two separate systems. The AJCC 8th-edition TNM classification is used for prognosis and reporting. The NCCN resectability classification (resectable, borderline resectable, locally advanced, or metastatic) is based on tumor contact with the major peripancreatic vessels, is assigned by multidisciplinary consensus, and determines initial management.^[19][3]

Systemic therapy is the backbone of management for nearly all patients, and germline and somatic tumor profiling are required before therapy is selected. For fit patients with metastatic disease, gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, and NALIRIFOX are preferred first-line options, and none has proven superior.^[3][20][21] In August 2026, the FDA approved daraxonrasib, an oral RAS(ON) inhibitor, for previously treated metastatic disease or for patients who are not candidates for multiagent therapy.^[22] Complete (R0) surgical resection is the only potentially curative treatment. Resectable disease is treated with upfront resection followed by 6 months of adjuvant modified FOLFIRINOX in fit patients, and borderline resectable disease receives neoadjuvant therapy first. Outcomes depend strongly on hospital volume.^[23][13][24] Smoking cessation is the highest-yield primary prevention measure, although risk approaches that of never-smokers only after about 15–20 years. No drug is recommended for chemoprevention outside a clinical trial.^[25][8] Secondary prevention focuses on nutrition, including pancreatic enzyme replacement therapy, and on palliation of pain, jaundice, and duodenal obstruction.

The pancreas was described in antiquity, but pancreatic cancer became a surgical disease only in the late 19th century. Modern care developed through three successive changes. The first was a survivable operation, pancreatoduodenectomy, developed by Kausch (1912) and popularized by Whipple (1935–1941). The second was the centralization of that operation in high-volume centers, which lowered operative mortality from roughly 25–33% in the post-Whipple decades to about 1–2% at the busiest institutions. The third was the arrival of effective multiagent, neoadjuvant, and biomarker-directed systemic therapy, culminating in the 2026 approval of the first RAS inhibitor for pancreatic adenocarcinoma.^{[4][26][5][27]} With multimodal therapy, 5-year survival after resection is now about 20–30%. That figure contrasts with the 5–8% often quoted in older teaching, although only about 15–20% of patients have resectable disease at diagnosis.^[28][6]

Pancreatic cancer is classified along three independent axes, each with its own prognostic and treatment implications: (1) histologic tumor type and cell of origin according to the WHO classification of digestive system tumors (5th edition, 2019, with 2026 refinements), which separates exocrine neoplasms, dominated by pancreatic ductal adenocarcinoma (PDAC; ~90%), from pancreatic neuroendocrine neoplasms; (2) grade, which for precursor lesions and neuroendocrine tumors now uses simplified, reproducible, proliferation-based tiers; and (3) anatomic extent by the American Joint Committee on Cancer (AJCC) 8th-edition TNM system, which uses separate schemes for exocrine adenocarcinoma and pancreatic neuroendocrine tumors.^{[2][29][3][30]} The most important changes from legacy teaching are the replacement of the three-tier pancreatic intraepithelial neoplasia (PanIN) system by a two-tier (low-grade/high-grade) scheme, Ki-67/mitotic grading of neuroendocrine tumors with recognition of a well-differentiated G3 category distinct from neuroendocrine carcinoma, and a size-based T category with node-count-based N category in AJCC 8.^[2][31][3]

Pancreatic cancer is the result of activation or inactivation of multiple gene subsets. The progression and development of pancreatic cancer is influenced by complex interactions and crosstalk between several cellular signaling pathways that include inactivation of tumor suppressor genes, activation of oncogenes and deregulation of molecules in various signaling pathways. EGFR, Akt, NF-kB and Hedgehog pathways are most commonly involved in the pathogenesis of pancreatic cancer. Majority of ductal adenocarcinomas have varying degrees of mucin production and duct-like structures and present as moderate-poorly differentiated masses. The ductal adenocarcinomas are referred to as “desmoplastic” or “scirrhous” carcinomas due to their characteristic dense stromal fibrosis occurring due to alterations in transforming growth factor-beta (TGF–beta) signaling. Local extension of tumor cells may occur into adjacent structures such as superior mesenteric vessels, perineural invasion both inside and outside the pancreas (eg, the retroperitoneum), duodenum, portal vein and stomach. Lymph node spread can occur to the regional peripancreatic, mesenteric, perigastric, portahepatic and omental lymph nodes.

Pancreatic ductal adenocarcinoma (PDAC) develops from somatic driver mutations that accumulate in steps, on a background of inherited and acquired predisposition. Four genes make up the core molecular signature of PDAC. The first is an activating KRAS mutation, found in about 85–95% of tumors. The other three are tumor suppressor genes that are inactivated: CDKN2A, TP53, and SMAD4. These alterations are acquired one after another as precursor lesions progress to invasive cancer.^{[7][8][32][33]} About 5–10% of unselected patients carry a pathogenic germline variant, most often in DNA damage repair genes. The proportion rises to about 30% in early-onset disease.^[10][8][12] Most PDAC is sporadic. Established acquired risk factors include cigarette smoking, obesity, long-standing type 2 diabetes, and chronic pancreatitis.^{[8][13][1][34]} The cause of a patient’s PDAC now shapes management. Universal germline testing is recommended for every patient with PDAC, and tumor profiling finds a minority with targetable alterations.^{[1][35][36][16]}

Pancreatic cancer must be differentiated from other pancreatic pathologies such as chronic pancreatitis, autoimmune pancreatitis, pancreatic pseudocyst, choledocholithiasis, and neuroendocrine tumors of the pancreas. Pathologies of the bile duct and duodenum such as choledocholithiasis, gallstones (cholelithiasis), choledochal Cysts, cholangiocarcinoma, bile duct strictures and ampullary cancer should be differentiated from pancreatic cancer based on imaging and biopsy findings. Metastasis from different sites and vascular causes such as abdominal aortic aneurysms may also mimic pancreatic cancer.

Pancreatic cancer is uncommon compared with other solid tumors but is extremely lethal. It is currently the third leading cause of cancer death in the United States and is projected to become the second by about 2030.^[9][1] About 90% of cases are pancreatic ductal adenocarcinoma (PDAC), so population statistics for pancreatic cancer largely reflect PDAC.^[1] In 2021, U.S. age-adjusted incidence was 18.7 per 100,000 and mortality was 15.8 per 100,000. These two rates are nearly the same, which reflects how poor the prognosis is.^[11] Five-year relative survival has risen from about 4% in 2000 to about 13%, but this is still among the lowest of any major cancer.^[8]

Incidence rises steeply after age 50 and is higher in men and in non-Hispanic Black individuals. Rates are highest in very-high Human Development Index (HDI) regions. Early-onset disease (diagnosis before age 50) is increasing in the U.S., mainly among women.^[9][37][12]

Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of pancreatic neoplasms.^[1] Its risk factors fall into three groups: modifiable lifestyle and metabolic factors, non-modifiable demographic factors, and inherited (germline) susceptibility. Most individual factors carry only a modest relative risk. The factors with the most clinical leverage are:

• Cigarette smoking, the dominant modifiable cause (~20% of cases).
• New-onset diabetes mellitus in older adults, which often reflects occult PDAC rather than causing it.
• High-penetrance hereditary syndromes.^[13][1]

Approximately 5–10% of unselected patients with PDAC carry a pathogenic germline variant. At least half of these carriers have no suggestive family history, which is the rationale for universal germline testing of all patients with PDAC.^[9][8]

The U.S. Preventive Services Task Force (USPSTF) recommends against screening for pancreatic cancer in asymptomatic, average-risk adults (Grade D). There is no evidence that screening, or treatment of screen-detected disease, reduces morbidity or mortality, and the harms are at least moderate.^[14]

Targeted surveillance is recommended for high-risk individuals. This group includes carriers of a pathogenic or likely pathogenic (P/LP) germline variant in a pancreatic cancer susceptibility gene and people with a qualifying family history, generally a lifetime risk above 5%. NCCN, ASGE, AGA, and the International Cancer of the Pancreas Screening (CAPS) Consortium recommend annual contrast-enhanced magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS), performed at experienced high-volume centers.^[16][15][38]

The case for surveillance in enriched populations rests on stage. Pancreatic ductal adenocarcinoma (PDAC) has a lifetime risk of only about 1.3%–1.7% in the general population. It is still the third-leading cause of U.S. cancer death, with about 13% overall 5-year survival. Most cases present at regional or distant stage, where 5-year survival is 3%–16%, whereas survival for stage IA disease approaches about 80%.^[17][39] About 10% of PDAC is attributable to hereditary predisposition, and current surveillance targets only this fraction of the disease burden.^[8][10]

Pancreatic ductal adenocarcinoma (PDAC) accounts for most pancreatic malignancies. It arises from precursor lesions through stepwise accumulation of KRAS, CDKN2A, TP53, and SMAD4 alterations.^[40] At the molecular level the disease develops over many years, but it progresses rapidly once clinically apparent.^[7] The major complications are:

• Biliary obstruction
• Gastric outlet/duodenal obstruction
• Cancer-related pain
• Exocrine pancreatic insufficiency
• Cachexia
• Venous thromboembolism (VTE)

Overall 5-year relative survival is about 12%. It is about 46% for localized disease and about 3% for distant disease.^[18]

Pancreatic ductal adenocarcinoma (PDAC) is staged with two complementary systems that should be kept separate. The AJCC 8th edition TNM classification (2017) is an anatomic and pathologic system used mainly for prognosis and standardized reporting. In the 8th edition, T category is defined chiefly by tumor size, N category by the number of involved nodes, and T4 by arterial involvement regardless of size.^[19] The clinical resectability classification of the NCCN has four tiers: resectable, borderline resectable, locally advanced, and metastatic. It is based on tumor contact with the peripancreatic arteries and veins on pancreas-protocol imaging, and it determines initial management.^[3][31] Biologic markers (CA 19-9, nodal disease) and conditional factors (performance status) are increasingly added to anatomic resectability.^[41] Staging should be done with dedicated pancreas-protocol cross-sectional imaging and finalized by multidisciplinary consensus at a high-volume center.^[3] Pancreatic neuroendocrine tumors have a separate AJCC staging system and are not covered here.^[42]

A positive history of cigarette smoking, alcoholism, diabetes mellitus, chronic pancreatitis and family history of pancreatic cancer are considered as risk factors for developing pancreatic cancer. The most common symptoms of pancreatic cancer include mid-epigastric pain, jaundice, sudden unexplained weight loss and dark urine and light-colored or greasy stools.

Patients with pancreatic cancer are usually in the sixth decade of life and appear cachectic, with signs of malnutrition. Patients mostly present with palpable abdominal mass, epigastric tenderness radiating to the back, hepatospleenomegaly and signs of metastasis in advanced stages. These signs of metastasis include left supraclavicular lymphadenopathy (Virchow’s node), palpable periumbilical mass (Sister Mary Joseph’s node), metastatic palpable mass in the rectal pouch (Blumer’s shelf) and the involvement of other nodes in the cervical area.

Laboratory findings in pancreatic cancer patients are often non specific and include abnormal liver function tests such as elevated serum bilirubin levels (conjugated and total), elevated alkaline phosphatase and gamma-glutamyl transpeptidase levels. Patients may have evidence of malnutrition, mild normocytic normochromic anemia and elevated CA 19-9 levels.

There are no chest X-ray findings associated with pancreatic cancer.

Findings on CT scan that may be suggestive of pancreatic cancer include morphological changes of the gland, destruction of the peripancreatic fat and loss of the sharp margins with surrounding structures, involvement of the regional lymph nodes and adjacent vasculature, pancreatic ductal dilatation, pancreatic atrophy and obstruction of the common bile duct . MDCT (Multi-detector row computed tomography) the imaging modality widely used in suspected pancreatic cancer patients as the pre-operative examination. MDCT is used as the primary imaging modality, and is used in conjunction with PET/CT. MDCT helps in local and distant disease assessment in a single scan. MDCT is useful in the evaluation of vascular involvement, which helps in predicting the tumor resectability.

MRI is considered when there is a diagnostic difficulty even after performing a CT scan. MRI is helpful in staging the extent and spread of pancreatic carcinoma rather than for detecting tumors or lesions less than 2 cm in size. MRI scan while determining pancreatic adenocarcinoma relies on the assessment of the size, shape, contour of the gland. MRI is helpful in characterizing cystic lesions of the pancreas and can aid in arriving at the diagnosis. MRI scan of the pancreas while assessing for pancreatic cancer presents as hypointense on T1-weighted images and hyperintense or isointense on T2-weighted images. During dynamic MR imaging, the tumor of pancreatic cancer in the early phase shows diminished enhancement and in the late phase shows gradual enhancement.

Pancreatic cancer has a variable appearance on USG. The appearance relative to normal pancreatic tissue may be hypoechoic, isoechoic or hyperechoic. In majority of the cases, an ill defined hypoechoic mass is seen infiltrating into a bright pancreatic parenchyma. Pancreatic and biliary duct dilatation is seen in case of carcinoma of the head of pancreas (Double duct sign). The disadvantage of a transabdominal USG is its inability to clearly demarcate lymphadenopathy, tumor margins and the relation of the tumor to vessels around the pancreas. Endoscopic Ultrasound (EUS) has a high efficacy in the detection of tumors smaller than 2 cm, for local T and N staging, and prediction of vascular invasion. It has a higher resolution than transabdominal ultrasound, due to the small distance between the endoscope and pancreas through the wall of the duodenum. EUS plays an important role in the preoperative staging of pancreatic cancer particularly in cases where CT evaluation suggests equivocal findings. Moreover, EUS-guided fine needle aspiration biopsy (FNA) is the best modality for obtaining a tissue diagnosis.

ERCP and PTC are other imaging techniques that can be used to diagnose pancreatic cancer.

There are no other diagnostic studies associated with pancreatic cancer.

Systemic therapy is the backbone of management for nearly all patients with pancreatic ductal adenocarcinoma (PDAC), including those with resectable disease, in whom chemotherapy is given before and/or after surgery. Universal germline testing and somatic tumor profiling are now required before therapy is selected. They identify candidates for platinum-based therapy, PARP inhibitor maintenance, tumor-agnostic targeted agents, and immunotherapy.^[3][21] For fit patients (ECOG 0–1) with metastatic disease, gemcitabine plus nab-paclitaxel, (modified) FOLFIRINOX, and NALIRIFOX are NCCN category 1 preferred first-line options, and none has proven superior to the others. Poorer performance status shifts treatment toward single agents or best supportive care.^[3][20] After upfront resection, 6 months of adjuvant modified FOLFIRINOX is preferred for fit patients. Neoadjuvant therapy is standard for borderline resectable disease.^[23][13] In August 2026 the FDA approved daraxonrasib, an oral RAS(ON) inhibitor, for metastatic disease after at least one prior systemic therapy or in patients who are not candidates for multiagent therapy.^[22]

Complete (R0) surgical resection is the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC). It is appropriate only for localized disease and is one part of multimodality therapy that nearly always includes systemic chemotherapy.^[35][1] A multidisciplinary team assigns resectability from pancreatic-protocol imaging. The four categories are resectable, borderline resectable, locally advanced, and metastatic, and they are defined mainly by tumor contact with the celiac axis, superior mesenteric artery, common hepatic artery, superior mesenteric vein, and portal vein.^[3][43]

For resectable disease, the standard approach is upfront resection followed by adjuvant chemotherapy. For borderline resectable disease, neoadjuvant therapy is given before resection.^[3][44] Venous resection with reconstruction is accepted when it achieves R0. Arterial resection is reserved for selected responders at expert centers.^[3][45] Outcomes depend strongly on hospital volume.^[24] Metastatic and unconvertible locally advanced disease are managed with endoscopic or surgical palliation, not resection.^[3]

Primary prevention of pancreatic ductal adenocarcinoma (PDAC) relies on modifying lifestyle and metabolic risk factors. No population-level screening test exists for average-risk adults, and most cases are diagnosed at an advanced, incurable stage.^[8][13] Inherited syndromes account for only about 5–10% of unselected cases; the rest reflects ageing, which cannot be modified, plus modifiable exposures.^[8][13] The modifiable factors with the strongest and most consistent evidence are:

• cigarette smoking
• excess adiposity
• dysglycemia and type 2 diabetes mellitus
• heavy alcohol use

Chronic pancreatitis strongly amplifies risk, and is itself partly driven by smoking and alcohol. Smoking cessation is the highest-yield intervention, but its benefit accrues slowly: risk approaches that of never-smokers only after about 15–20 years of abstinence.^[25][46] No drug is recommended for PDAC chemoprevention outside a clinical trial.^[8]

Secondary prevention of pancreatic cancer involves proper diet based on American Cancer Society (ACS) guidelines and palliative therapy for patients. Malabsorption may arise when pancreatic duct obstruction leads to exocrine pancreatic insufficiency. The diet proposed for pancreatic cancer patients is based on ACS guidelines and advocates administration of pancreatic enzyme replacement therapy, avoidance of high-protein/high-fat diets, individualized dietary prescriptions from a registered dietitian and dietary supplementation with omega-3 fatty acids. Palliative therapy is considered as an important part of secondary prevention and includes adequate analgesia, treatment of jaundice and duodenal obstruction, arising as complications of surgery.

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