Pancreatic cancer historical perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Sudarshana Datta, MD [3]

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]

• 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]}

• 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.

• 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]