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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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.^[1][2][3][4] 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.^[5][6]

• Herophilus of Chalcedon (~300 BC) first described the pancreas. Rufus of Ephesus (~100 AD) named it, from the Greek pan (all) and kreas (flesh). Its ductal anatomy (Wirsung, Santorini) and exocrine physiology (de Graaf; later the discovery of trypsin and lipase) were characterized between the 17th and 19th centuries.^[7][8]
• By the late 19th century, the clinical features and histology of pancreatic cancer had been described. Ductal, acinar, and islet cell cancers were distinguished as separate entities.^[7]
• A palpable, nontender gallbladder in malignant distal biliary obstruction became known as Courvoisier’s sign.
• Pancreatic surgery began in the mid-19th century with drainage procedures. Distal resections followed in the late 1800s, and resection of the pancreatic head, which was far more hazardous, developed step by step between 1898 and 1935.^[8]

Key milestones in pancreatic cancer surgery

Year	Surgeon(s)	Milestone
1882	Trendelenburg	First successful excision of a solid pancreatic tumor (distal)[7][1]
1887	Kappeler	Cholecystojejunostomy as palliative biliary bypass for pancreatic cancer[7]
1898	Halsted	First successful local resection of an ampullary (periampullary) tumor[1]
1898	Codivilla	En bloc resection of the pancreatic head and duodenum (patient did not survive long-term)[1][9]
1909/1912	Kausch	First successful two-stage partial pancreatoduodenectomy, hence the eponym Kausch–Whipple procedure[1][2][9]
1935	Whipple, Parsons, Mullins	Three patients presented to the American Surgical Association; two-stage procedure (biliary diversion/gastrojejunostomy, then resection)[1][9]
1940–1941	Whipple	One-stage pancreatoduodenectomy with pancreaticojejunostomy[1][9][10]
1944; late 1970s	Watson; Traverso and Longmire	Pylorus-preserving pancreatoduodenectomy introduced and then popularized[11]
1994	Gagner and Pomp	First laparoscopic pancreatoduodenectomy[12]

• The operation became survivable only after two advances. The discovery of vitamin K allowed correction of the coagulopathy of obstructive jaundice, and blood typing and blood banking made major blood loss survivable. Before these advances, early attempts were frequently fatal.^[2]
• The classic operation removes the pancreatic head, duodenum, distal common bile duct, gallbladder, and distal stomach. Reconstruction uses pancreatico-, hepatico-, and gastrojejunostomy. Meta-analysis shows no meaningful difference in morbidity or mortality between the classic and pylorus-preserving variants.^[11][10]
• The oncologic goal has been the same since Whipple: a margin-negative (R0) resection. R0 is now increasingly defined as a tumor-free margin of at least 1 mm, although definitions vary internationally.^[13][14]

For about 25 years after Whipple’s reports, operative mortality stayed near 25–33%. This led to widespread surgical nihilism and underuse of resection.^[2][9] In the 1980s and 1990s, care was concentrated in high-volume centers with better perioperative and critical care and interventional radiology. Mortality fell below 5%, and to about 1–2% at the busiest institutions.^{[8][3][5][9][15]}

Secular trends in short-term mortality after pancreatoduodenectomy

Era / dataset	Mortality	Source
1940s–1970s (post-Whipple)	~25–33%	[2][9]
Sweden, 1960s → 2010–2016	17.2% → 1.6%	[6]
US NCDB (pancreatic adenocarcinoma), 2004 → 2020 (90-day)	8.0% → 5.3%	[16]
ACS-NSQIP, 2006 → 2016 (30-day)	2.9% → 1.5%	[17]
Contemporary high-volume centers	~1–2% or lower	[3][18]

• Recent mortality reductions have come mainly from better rescue of patients once complications occur (less “failure to rescue”), through timely ICU escalation and interventional management. The incidence of major complications has stayed relatively stable.^[17][19]
• The volume–outcome benefit appears to plateau at roughly 40–50 procedures per year. It is much stronger for pancreatoduodenectomy than for distal pancreatectomy.^[20][21][22]
• Access to high-volume centers still differs by race, socioeconomic status, and geography.^[23]

Minimally invasive pancreatoduodenectomy, now mostly robotic, has expanded substantially. Its rate in ACS-NSQIP roughly doubled over the past decade. Compared with laparoscopy, the robotic approach has lower conversion and positive-margin rates. Thirty-day mortality and complication rates have remained stable, and no approach has been shown to be superior to open surgery.^[12][24][25]

For most of the 20th century, systemic options were negligible and advanced disease was managed palliatively. Effective systemic therapy is a development of the past three decades.

Landmark developments in systemic therapy

Year	Development	Key finding
1997	Gemcitabine monotherapy	Became the first-line standard after showing clinical benefit and a modest survival advantage over fluorouracil[26][14]
2000s	Erlotinib + gemcitabine	First targeted (EGFR) combination; only marginal benefit over gemcitabine alone[27][28]
2000s–2010s	Adjuvant trials (CONKO-001, ESPAC-3, ESPAC-4)	Adjuvant gemcitabine beat observation; 5-FU/leucovorin was roughly equivalent to gemcitabine; gemcitabine–capecitabine was superior[13][29]
2011	FOLFIRINOX (PRODIGE 4/ACCORD 11)	Metastatic disease: median OS 11.1 vs 6.8 months vs gemcitabine (HR 0.57)[26][30][27]
2013	Gemcitabine + nab-paclitaxel (MPACT)	Metastatic disease: median OS 8.5 vs 6.7 months vs gemcitabine (HR 0.72)[28][31]
2018	Adjuvant modified FOLFIRINOX (PRODIGE 24/CCTG PA.6)	Median OS ~54 vs ~35 months vs adjuvant gemcitabine; current adjuvant standard for fit patients[13][29]
2019	Olaparib maintenance (POLO)	Germline BRCA1/BRCA2 became the first predictive biomarker in pancreatic cancer; maintenance therapy after platinum-based chemotherapy[32][33]
2020s	Neoadjuvant therapy (PREOPANC series)	Practice shifted toward upfront systemic therapy for borderline resectable and selected resectable disease[34][35]
2023	NALIRIFOX (NAPOLI-3)	Metastatic disease: median OS 11.1 vs 9.2 months vs gemcitabine–nab-paclitaxel; no clear advantage over FOLFIRINOX on cross-trial comparison[26][14][13]
2010s–2020s	Tumor-agnostic targeted agents	Pembrolizumab (MSI-H/dMMR, TMB-H), dabrafenib–trametinib (BRAF V600E), NTRK fusion inhibitors (larotrectinib, entrectinib), selpercatinib (RET fusion)[4][13]
2026	Daraxonrasib (RASolute 302)	FDA-approved August 26, 2026 as the first RAS-targeted therapy for metastatic pancreatic adenocarcinoma, for patients after at least one prior systemic therapy or who cannot receive multiagent therapy[36][31]

• Because of this progression, germline and somatic profiling (BRCA1/BRCA2, PALB2, MSI/MMR, KRAS, BRAF, NTRK/RET fusions) is now standard practice.^[4][13]
• Resectability, once defined only by anatomic vessel involvement, is increasingly defined by tumor biology as well, including CA 19-9 levels and response to neoadjuvant therapy.^[14]
• Whether neoadjuvant therapy benefits clearly resectable disease is still debated. Randomized evidence is stronger for borderline resectable and locally advanced disease.^[35][37]

Nineteenth-century “islet cell” terminology gave way to a series of WHO classifications (2010, 2017, 2019, and the 2022 endocrine classification). These incorporated the Ki-67 proliferation index and established the current separation of well-differentiated neuroendocrine tumors (NET G1–G3) from poorly differentiated neuroendocrine carcinomas (NEC) and mixed neoplasms (MiNEN).^[38][39][40] Pancreatic NETs behave more indolently than ductal adenocarcinoma, which led the AJCC 8th edition to adopt a separate staging system for them.^[39]

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.^[1][2][3][4] 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.^[1][5][3]

The WHO classification is based on cell lineage and morphology and is the core element of pathology reporting.^[2] Correct subtyping matters because subtypes differ in prognosis, treatment response, and molecular profile.^[2]

Tumor type	Key features
Ductal adenocarcinoma (PDAC), NOS	~90% of pancreatic malignancies; glandular/duct-forming morphology with desmoplastic stroma[2]
PDAC subtypes	Colloid (mucinous non-cystic) carcinoma; poorly cohesive/signet ring cell carcinoma; medullary carcinoma; adenosquamous carcinoma; hepatoid carcinoma; undifferentiated carcinoma, including undifferentiated carcinoma with osteoclast-like giant cells (replaces the term “giant cell tumor”); large-cell carcinoma with rhabdoid phenotype[2]
Acinar cell carcinoma	<2% of adult pancreatic cancers; acinar differentiation (trypsin, chymotrypsin, BCL10 positive)[2]
Mixed carcinomas	Mixed acinar–ductal, mixed acinar–neuroendocrine, and mixed acinar–neuroendocrine–ductal carcinomas[2]
Pancreatoblastoma	Most common pancreatic malignancy of childhood; characterized by squamoid nests[2]

2026 WHO updates:^[6]

• Micropapillary carcinoma is now a morphologic pattern rather than a distinct PDAC subtype.
• Hepatoid morphology remains a recognized PDAC subtype but is also acknowledged in well-differentiated neuroendocrine tumors and solid pseudopapillary neoplasms.
• Grading guidance for treatment-naïve PDAC has been expanded.
• Acinar cell cystadenoma has been reclassified as non-neoplastic “acinar cystic transformation.”^[1]

PanIN is a microscopic (<0.5 cm), non-invasive ductal lesion and the principal precursor of PDAC.^[7][8] Per the 2014 Baltimore Consensus and the WHO 2019/2026 classifications, PanIN is graded in two tiers, replacing the legacy PanIN-1/2/3 system; the change was driven by better interobserver reproducibility and clinical relevance.^[5][9][7]

Grade	Legacy equivalent	Histology	Clinical significance
Low-grade PanIN	PanIN-1A, 1B, and 2	Flat or papillary mucinous epithelium; basal or pseudostratified nuclei; mild-to-moderate cytologic atypia	Very common, including in young and otherwise normal pancreata; the vast majority never progress[9][5]
High-grade PanIN	PanIN-3 / carcinoma in situ	Complex papillary/micropapillary architecture, cribriforming, budding, loss of nuclear polarity, severe atypia, mitoses	Rare (<5% of benign pancreata); usually adjacent to invasive PDAC; direct precursor of invasive cancer; staged as Tis[9][5][3]

• Intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), intraductal oncocytic papillary neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN) are all graded on the same two-tier (low-grade vs high-grade) dysplasia scale.^[1]
• IOPN and ITPN are now separated from conventional IPMN on the basis of distinct genomics and morphology.^[1]

KRAS mutation is a near-universal early event in PanIN. CDKN2A loss appears at the low- to high-grade transition. TP53 and SMAD4 inactivation are late events associated with invasion.^[9][10]

PanNENs account for up to ~7% of pancreatic tumors.^[11] The WHO framework separates well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinoma (NEC), a distinction with major molecular, prognostic, and therapeutic consequences.^[12][4] Neuroendocrine differentiation is confirmed by two of three markers: synaptophysin, chromogranin A, and INSM1.^[4]

NETs are graded by whichever of Ki-67 index or mitotic rate places the tumor in the higher category.^[4]

Category	Differentiation	Mitotic rate (per 2 mm²)	Ki-67 index
NET G1	Well differentiated	<2	<3%
NET G2	Well differentiated	2–20	3–20%
NET G3	Well differentiated	>20	>20%
NEC (small-cell or large-cell type)	Poorly differentiated	>20	>20%

^[1][4]

• NET G3 vs NEC: Recognition of well-differentiated NET G3 (Ki-67 >20% with retained neuroendocrine morphology) as distinct from poorly differentiated NEC is the pivotal change of the 2017 endocrine and 2019 digestive WHO classifications. NEC is high grade by definition and not formally graded.^[13][14][4] In difficult cases, an immunohistochemical panel including Rb, p53, p16, ATRX, and DAXX helps separate the two.^[4]
• Proposed G2 subdivision: G2a (Ki-67 3–10%) and G2b (>10–20%) improves prognostic stratification but has not been adopted in formal WHO grading.^[15][16]

Functioning PanNETs are defined by a clinical hormonal syndrome. Hormone immunohistochemistry does not establish functional status.^[4] Most PanNETs are sporadic, but syndromic associations (MEN1, von Hippel-Lindau disease, and less commonly neurofibromatosis type 1 and tuberous sclerosis) should be considered.^[11]

Tumor / syndrome	Hormone / biomarker	Typical location	Key features
Insulinoma	Insulin, proinsulin, C-peptide	Evenly distributed	Whipple triad (fasting hypoglycemia, neuroglycopenia, relief with glucose); usually small and benign[11][13]
Gastrinoma (Zollinger–Ellison syndrome)	Gastrin	Gastrinoma triangle; often duodenal/extrapancreatic	Refractory peptic ulcers, diarrhea, GERD; associated with MEN1[11]
Glucagonoma	Glucagon	Body/tail; often large	Necrolytic migratory erythema, diabetes, weight loss, stomatitis[11]
VIPoma (Verner–Morrison/WDHA)	VIP	Body/tail	Watery diarrhea, hypokalemia, achlorhydria[11]
Somatostatinoma	Somatostatin	Head/periampullary	Gallstones, diabetes, steatorrhea[11]
Nonfunctioning PanNET (includes former “PPoma”)	Chromogranin A ± pancreatic polypeptide	Often head	No hormonal syndrome; most common PanNET; larger at diagnosis with higher metastatic rate; PP elevation is not a clinical syndrome[11][4]

AJCC 8 made the T category size-based for T1–T3, dropped the ambiguous “extension beyond the pancreas” criterion, subdivided N by number of positive nodes, and removed the MX designation.^[17][18][3]

Category	Definition
Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ, including high-grade PanIN and IPMN, ITPN, or MCN with high-grade dysplasia
T1	≤2 cm (T1a ≤0.5 cm; T1b >0.5 to <1 cm; T1c 1–2 cm)
T2	>2 to ≤4 cm
T3	>4 cm
T4	Involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size
Regional lymph nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1–3 regional lymph nodes
N2	Metastasis in ≥4 regional lymph nodes
Distant metastasis (M)
M0	No distant metastasis
M1	Distant metastasis

^[3][17][18]

Stage	T	N	M
IA	T1	N0	M0
IB	T2	N0	M0
IIA	T3	N0	M0
IIB	T1–T3	N1	M0
III	T1–T3 Any T4	N2 Any N	M0
IV	Any T	Any N	M1

^[3][17]

Validation:

• In a multi-institutional validation, AJCC 8 distributed patients more evenly across stages and improved T-stage reproducibility compared with AJCC 7, which placed ~68% of resected patients in stage IIB.^[19]
• International validation confirmed modestly better overall stratification. The improvement came mainly from the node-count N category. The size-based T category discriminated poorly among node-negative patients.^[20][19]

AJCC 8 uses a separate staging system for well-differentiated PanNETs, distinct from PDAC and aligned with ENETS. PDAC size cutoffs and the PDAC celiac/SMA-based T4 definition should not be applied to NETs.^[11][12]

Category	Definition
T1	<2 cm, confined to pancreas
T2	2–4 cm
T3	>4 cm, or invading duodenum or common bile duct
T4	Invading adjacent organs or vessels
M1a	Hepatic metastasis only
M1b	Extrahepatic metastasis only
M1c	Both hepatic and extrahepatic metastases

^[11][12]

• PDAC (CAP synoptic protocol, NCCN-endorsed): Report WHO histologic type, histologic grade, full TNM, margin clearance in mm (“close” = within 1.0 cm), lymphovascular and perineural invasion, number of involved and examined nodes, and a tumor regression score after neoadjuvant therapy.^[3]
• High-grade PanIN at a margin: Document its presence at the neck/duct margin; on frozen section it may prompt more extensive resection.^[8]
• PanNET: Report the specific Ki-67 percentage (not a range) from hot-spot counting of ≥500 cells, the actual mitotic rate, and the classification system used. A diagnosis of “neuroendocrine tumor” without a grade is inadequate for management. When Ki-67 and mitotic rate are discordant, assign the higher grade.^[4] Ki-67 is more reproducible and prognostic than mitotic count.^[4][21]

• The size-based AJCC 8 T category underperforms as an independent prognostic discriminator in node-negative resected PDAC. Validation studies disagree on whether the 8th or 7th edition better predicts overall survival.^[20][19][22]
• Tumor regression grading after neoadjuvant therapy is not standardized. CAP and MD Anderson systems coexist, with limited reliability, especially in partial responders.^[6]
• Distinguishing NET G3 from NEC can be difficult because proliferation overlaps. The diagnosis depends on morphology plus ancillary markers and has different treatment implications.^[13][4]

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.^[1][2][3][4] 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.^[5][2][6] Most PDAC is sporadic. Established acquired risk factors include cigarette smoking, obesity, long-standing type 2 diabetes, and chronic pancreatitis.^[2][7][8][9] 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.^{[8][10][11][12]}

Exome and whole-genome sequencing consistently find four recurrently altered driver genes in PDAC, often called the genomic “mountains.” Alongside them is a long tail of low-frequency “hills.” The average PDAC exome carries only about 40 somatic mutations, which is a low burden for an adenocarcinoma.^[1][4][13]

Core somatic driver genes in pancreatic ductal adenocarcinoma

Gene (locus)	Class	Approximate frequency	Mechanism and timing	Clinical relevance
KRAS (12p)	Oncogene	~85–95%	Activating point mutation, most often at codon 12, less often at codons 13 and 61. It is the earliest, initiating event and is already present in low-grade PanIN. It drives MAPK/ERK signaling.	G12D is the most common variant and is associated with worse survival. G12R is enriched in early-stage disease. G12C is rare but can be targeted with KRAS G12C inhibitors. About 8–13% of tumors are KRAS wild-type, and these are enriched for targetable gene fusions.[1][2][3][7][14]
CDKN2A (9p21; p16)	Tumor suppressor	~60–95% (up to ~95% when deletion and methylation are counted)	Inactivated by homozygous deletion (~40%), loss of heterozygosity plus mutation (~40%), or promoter hypermethylation (~15%). Loss follows KRAS mutation.	When the 9p21 deletion also removes the neighboring interferon gene cluster, the tumor microenvironment becomes immunologically “cold.” Deletion and methylation are missed by mutation-only panels.[4][15][16]
TP53 (17p)	Tumor suppressor	~70–85%	Missense mutation with loss of the second allele. It is a late event, appearing in high-grade PanIN, and drives genomic instability.	Associated with a tendency to metastasize.[3][4][13][15]
SMAD4/DPC4 (18q)	Tumor suppressor	~20–55%	Homozygous deletion, or loss of heterozygosity plus mutation. It is a late event and disrupts TGF-β signaling.	Loss predicts a higher metastatic burden and worse prognosis.[2][3][4][15]

Several low-frequency drivers are biologically and clinically important:^[1][4][13]

• Homologous recombination repair genes: BRCA1, BRCA2, PALB2, and ATM
• Chromatin remodeling genes: ARID1A, KDM6A, PBRM1, and SMARCA4
• TGF-β pathway components: TGFBR2, ACVR1B, and ACVR2A
• GNAS and RNF43: characteristic of PDAC that arises from intraductal papillary mucinous neoplasms (IPMNs)

These drivers fit together into a small number of core signaling pathways. That pathway-level map has replaced older descriptions of nonspecific “deregulation” of signaling molecules.^[17][18] Whole-genome analyses also detect large-scale structural events. These include copy-number changes, chromothripsis, and kataegis, which are clusters of substitutions associated with APOBEC enzymes.^[13] Prognosis and treatment selection can be refined beyond single-gene status in two further ways. Transcriptomic subtyping separates classical from basal-like tumors. Whole-genome structural classes divide tumors into stable, scattered, and unstable groups.^[2][8]

About 85–95% of PDACs arise from pancreatic intraepithelial neoplasia (PanIN). About 15–20% arise from macroscopic cystic precursors, most often IPMNs.^[14][4][7] The cell of origin is still debated. Genetic and mouse-model data support acinar-to-ductal metaplasia triggered by oncogenic KRAS activation.^[14][4] The classic sequence starts with KRAS mutation in low-grade PanIN. CDKN2A inactivation follows, and TP53 and SMAD4 loss occur in high-grade lesions.^[2][19][8] Low-grade PanINs are present in 75–85% of adult pancreata, and nearly all of them harbor KRAS mutations, yet very few progress. Progression requires tumor suppressors to be lost one after another over decades. The lesion must also escape immune surveillance and overcome a stroma that does not support tumor growth.^[2]

About 5–10% of unselected PDAC patients carry a pathogenic germline variant. The figure is about 30% in early-onset disease.^[5][2][6] About half of carriers have no family history of the disease.^[10]

Hereditary predisposition to pancreatic ductal adenocarcinoma

Syndrome or pathway	Gene(s)	Key points
Homologous recombination repair deficiency, including hereditary breast and ovarian cancer syndrome	BRCA2, BRCA1, PALB2, ATM	BRCA2 confers the strongest risk among the common genes (OR ~9), and ATM confers a similar risk (OR ~9). These variants predict sensitivity to platinum chemotherapy and PARP inhibitors.
Familial atypical multiple mole melanoma	CDKN2A	Among the highest relative risks. Surveillance is recommended regardless of family history.
Peutz-Jeghers syndrome	STK11	Among the highest relative risks. Surveillance is recommended regardless of family history.
Lynch syndrome	MLH1, MSH2, MSH6, PMS2, EPCAM	Produces MSI-high/dMMR tumors that respond to immune checkpoint inhibitors.
Li-Fraumeni syndrome	TP53	Rare germline cause.
Hereditary pancreatitis	PRSS1, SPINK1	Lifetime risk of up to ~40%, driven by recurrent inflammation.[5][8][20][10]

Most PDAC is sporadic. The established acquired risk factors are summarized below; see Pancreatic cancer risk factors for more detail.^[2][7][8][9]

Factor	Comments
Cigarette smoking	The leading modifiable risk factor. Risk falls after quitting.
Obesity (BMI ≥30)	Metabolic syndrome carries an RR of ~1.3.
Long-standing type 2 diabetes	Diabetes that starts after age 50 can be an early sign of hidden PDAC. About 0.3–1% of these patients are diagnosed with PDAC within 3 years.
Chronic pancreatitis	The association is strongest close to the time of diagnosis. Some of it may reflect pancreatitis caused by a tumor that has not yet been found.[13]
Heavy alcohol use (≥3 drinks/day)	The effect is largely mediated through pancreatitis.
Other	Non-O ABO blood group, tall height, and diets high in red or processed meat. Associations with certain chronic infections are supported only by modest-quality evidence.[7][9][6]

• Universal germline testing: NCCN and ASCO recommend germline testing for every patient with newly diagnosed PDAC, whether or not there is a family history. Testing should use a multigene panel that includes BRCA1/2, PALB2, ATM, CDKN2A, STK11, and the mismatch repair genes (NCCN category 2A).^{[8][10][11][12]} Testing only patients with a family history misses about half of carriers.^[10]
• Somatic tumor profiling: Recommended in locally advanced or metastatic disease to look for actionable alterations. These include BRCA1/2 and PALB2 (platinum or PARP inhibitors), MSI-H/dMMR (immunotherapy), KRAS G12C, and rare NTRK or other fusions. KRAS wild-type tumors should be profiled with particular care.^[11][8][18] Even so, matched targeted therapy applies to fewer than 5% of PDACs.^[18]
• Risk modification: Counsel patients on quitting smoking. In adults aged 50 or older with new-onset diabetes and other suggestive features, evaluate for an occult malignancy.^[2][7]
• Cascade testing and surveillance: Refer high-risk germline carriers for surveillance; see Pancreatic cancer screening.^[12][20]

• Whether PDAC originates from acinar or ductal cells remains unresolved.^[14][4]
• It is disputed whether heavy alcohol use is an independent risk factor or acts only through pancreatitis.^[8][9]
• Guidelines differ on surveillance eligibility for BRCA1, ATM, and PALB2 carriers who have no family history.^[20][12]
• Germline risk profiles vary by ancestry. For example, BRCA1/2, ATM, and CDKN2A variants are less frequent in Asian cohorts, which limits how widely a single panel applies.^[21]

Pancreatic cancer must be distinguished from other pancreatobiliary pathologies that cause abdominal pain and jaundice such as acute suppurative cholangitis, acute cholecystitis, cholelithiasis, chronic pancreatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Pancreatic cancer must also be differentiated from other pancreatic pathologies such as autoimmune pancreatitis, pancreatic pseudocyst, 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 may also be distinguished from other causes of abdominal pain and jaundice as depicted in the table below:

Classification of pain in the abdomen based on etiology Disease Clinical manifestations Diagnosis Comments Symptoms Signs Fever Rigors and chills Abdominal Pain Jaundice Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Abdominal causes Inflammatory causes Pancreato-biliary disorders Acute suppurative cholangitis + + RUQ + + + + N Abnormal LFT WBC >10,000 Ultrasound shows biliary dilatation/stents/tumor Septic shock occurs with features of SIRS Acute cholangitis + − RUQ + − − − N Abnormal LFT Ultrasound shows biliary dilatation/stents/tumor Biliary drainage (ERCP) + IV antibiotics Acute cholecystitis + − RUQ + − − − Hypoactive Hyperbilirubinemia Leukocytosis Ultrasound shows gallstone and evidence of inflammation Murphy’s sign Acute pancreatitis + − Epigastric ± ± − − N Increased amylase / lipase Ultrasound shows evidence of inflammation Pain radiation to back Primary biliary cirrhosis − − RUQ/Epigastric + − − − N Increased AMA level, abnormal LFTs Primary sclerosing cholangitis + − RUQ + − − − N Increased liver enzymes Increased IgM, IgG4 Anti-neutrophil cytoplasmic antibody (p-ANCA) Anti-nuclear antibody (ANA) Anti-smooth muscle antibody (Anti-Sm) Anti-endothelial antibody Anti-cardiolipin antibody Cholelithiasis ± − RUQ/Epigastric ± − + + N to hyperactive for dislodged stone Leukocytosis Ultrasound shows gallstone Murphy’s sign Pancreatic cancer − − Epigastric ± − − − N Elevated serum bilirubin (conjugated and total) Elevated alkaline phosphatase levels Elevated gamma-glutamyl transpeptidase levels Normal/elevated aspartate aminotransferase and alanine aminotransferase Serum amylase and/or lipase levels are normal/elevated mild normocytic normochromic anemia Thrombocytosis CT shows 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 Obstruction of the common bile duct (CBD) USG shows:  ill defined hypoechoic mass is seen infiltrating into a bright pancreatic parenchyma  EUS-guided fine needle aspiration biopsy (FNA) is the best modality for obtaining a tissue diagnosis. Signs of metastatic disease 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) Involvement of other nodes in the cervical area Gastric causes Gastrointestinal perforation + ± Diffuse ± + + ± WBC> 10,000 Air under diaphragm in upright CXR Intestinal causes Whipple’s disease ± − Diffuse ± ± − − N Thrombocytopenia Hypoalbuminemia Small intestinal biopsy for Tropheryma whipplei *Endoscopy is used to confirm diagnosis. Images used to find complications Chest and joint x-ray CT MRI Echocardiography Extra intestinal findings: Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Arthritis Ascites Celiac disease − − Diffuse ±, also dermatitis herpetiformis − − − Hyperactive (increased sounds) IgA endomysial antibody IgA tissue transglutaminase antibody Anti-gliadin antibody Hepatic causes Viral hepatitis + − RUQ + − + Liver masses + + in Liver abscess RUQ ± + in sepsis Budd-Chiari syndrome ± − RUQ − Hemochromatosis − − RUQ ± + in cirrhotic patients may be in cardicmyopathy − − >60% TS >240 μg/L SF Raised LFT Hyperglycemia Ultrasound shows evidence of cirrhosis Extra intestinal findings: hyperpigmentation Diabetes mellitus Arthralgia Impotence in males Cardiomyopathy Atherosclerosis Hypopituitarism Hypothyroidism Extrahepatic cancer Prone to specific infections Cirrhosis + − RUQ + − Peritoneal causes Spontaneous bacterial peritonitis + − Diffuse + in cirrhotic patients ± − − Hypoactive Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism Ultrasound for evaluation of liver cirrhosis Hollow Viscous Obstruction Biliary colic − − RUQ + − − − N Increased bilirubin and alkaline phosphatase Ultrasound Nausea & vomiting

Pancreatic carcinoma should be differentiated from other diseases presenting with weight loss, nausea, vomiting, diarrhea, fatigue and abdominal pain. The differentials include the following:

Disease	Clinical manifestations													Diagnosis		Comments
	Symptoms									Signs
	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Chronic pancreatitis	Epigastric	−	−	±	±	−	+	+	−	−	−	−	N	Increased amylase / lipase Increased stool fat content Pancreatic function test	CT scan Calcification Pseudocyst Dilation of main pancreatic duct	Predisposes to pancreatic cancer
Pancreatic carcinoma	Epigastric	−	−	+	+	−	+	+	−	−	−	−	N	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with  PET/CT MRI	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau’s syndrome) Pancreatic panniculitis
Dumping syndrome	Lower and then diffuse	−	−	+	−	−	+	+	−	+	−	−	Hyperactive	Glucose challenge test Hydrogen breath test	Upper GI series Gastric emptying study	Postgastrectomy

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

To review a comprehensive differential diagnosis of diseases presenting with abdominal pain, click here.

The differentials for pancreatic cancer mainly involve pathologies of the pancreas, bile duct, duodenum, lymphovascular tissue or metastasis from other sites. It is difficult to differentiate pancreatic cancer from other neoplasms as they all present with non specific constitutional symptoms. Hence, differentiation is primarily based on anatomic location:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]}

Origin	Disease	Diagnostic study of choice
Pancreas	Chronic pancreatitis Autoimmune pancreatitis Pseudocyst of pancreas Pancreatic cyst Neuroendocrine tumors of pancreas Gastrinoma VIPoma Somatostatinoma Insulinoma	Imaging: Non-contrast helical CT Biopsy findings Serum IgG4 levels for autoimmune pancreatitis For pancreatic NETs: Gastrin levels Somatostatin levels Insulin levels Serum electrolytes
Bile duct	Choledocholithiasis Gallstones (Cholelithiasis) Choledochal Cysts Cholangiocarcinoma Bile duct strictures Cholangitis Cholecystitis	Imaging: MRI MRCP USG bile duct ERCP Biopsy findings
Duodenum	Ampullary cancer Duodenal cancer	Imaging: MRI ERCP Upper GI Endoscopy Biopsy findings
Lymphovascular tissue	Abdominal aortic aneurysm Intestinal ischemia Lymphomas Gastric Pancreatic	Imaging: MRI MR Angiography CT Angiography Biopsy for lymphoma
Metastasis	Skin(Melanoma) Kidney Breast Colon Liver(Hepatocellular carcinoma) Stomach	Imaging: MRI PET scan CT Biopsy Specific markers for different cancers: HCC: AFP Breast: BRCA 1 and 2 Colon cancer: CEA Melanoma: S100