Whipple's Whipples: Insulinomas Changed the Course of Hepatopancreatobiliary Surgery

Descriptions of the pancreas gland can be traced back to ancient medicine. In 1500 BCE Egypt, the Ebers Papyrus described the clinical features of diabetes mellitus. In the 4th century BCE, the Greek physician Herophilus, known as “the Father of Anatomy,” described a nameless, glandular structure in the retroperitoneum.^1,2 In the 1st century CE, Greek physician Aretaeus of Cappadocia provided the first named description of diabetes mellitus. In 100 CE, Rufus of Ephesus first named the pancreas (from the Greek pan “all” and creas “flesh”).1,2 In the 2nd century CE, the prominent Roman physician Galen described the pancreas in his writings as an attachment for the omentum.^1,2

In 1541, the famed Dutch anatomist Vesalius described the pancreas briefly as a “glandulous body” in his text Epitome, though he did not postulate its function or utility.¹ He wrote, “The stem [of the portal vein] is divided into two trunks; the right one [the superior mesenteric vein], which is larger, is carried in various ways through the mesentery and is offered to the intestines (first the duodenal intestine); the right trunk also presents a branch to the beginning of the jejunum. The right trunk is supported by a glandulous body stretched out in this region of the intestines.”

The pancreatic duct was first described by Dutch anatomist Johann Wirsung in 1642.¹ Wirsung wrote of the duct, “Should I call it an artery or a vein? I never found blood in it, but a turbid fluid which stains a silver probe like bile. What this may be, what function and action it has, is unclear, and I do not know.” Ironically, this ductular structure that Wirsung did not know the function of would later be eponymously named after him.

Early Pancreatic Operations from Surgical Pioneers

The earliest described pancreatic resections were performed by some of the foremost surgeons of their times; however, the surgeons were met with significant obstacles. One of the first documented attempts at pancreatic resections was by Friedrich Trendelenburg (1844–1924, Germany), who performed a distal pancreatectomy with splenectomy for a spindle cell mass in 1882. The patient died on the first postoperative day.³ In 1884, Theodor Billroth (1829–1894, Switzerland) attempted two partial pancreatic resections.³ In 1886, Nicholas Senn, MD (1844–1908, US), described various operations of the pancreas in his writings, which included “Complete Section of the Pancreas,” “Complete Extirpation of the Pancreas,” “Partial Extirpation of the Pancreas,” and “External Pancreatic Fistula.”⁴ However, Dr. Senn noted the near impossibility of removing the entire pancreas due to pancreatic exocrine insufficiency, hemorrhage from the duodenum, and duodenal ischemia.

In 1895, Emil Theodor Kocher (1841–1917, Switzerland) described a successful transduodenal retrieval of periampullary choledocholithiasis and later described his eponymous lateral mobilization of the duodenum in 1903. In 1899, William Stewart Halsted, MD, FACS(Hon) (1852–1922, US), described the first successful resection of an ampullary carcinoma at a meeting of the Suffolk Medical Society.⁵ These incremental milestones in surgical technique and perioperative management paved the way for later innovations in pancreatic surgery.

Walther Kausch: An Uncredited Innovator

Walther Kausch, MD (1867–1928, Germany), is a lesser-known innovator in the history of the pancreatoduodenectomy. In fact, Dr. Kausch performed the first pancreatoduodenectomy in 1909, more than 25 years before renowned American surgeon Allen Oldfather Whipple, MD, FACS (1881–1963), performed his operation.

Dr. Kausch was born in Königsberg, Prussia, and completed his medical education in Strasbourg in 1890. Following his initial training in psychiatry and internal medicine, he was recruited to Breslau by Jan Mikulicz-Radecki, MD, to complete his surgical training. (Dr. Kausch would later marry Dr. Mikulicz-Radecki’s daughter.) Afterward, he moved to Berlin to become chair of surgery at the Auguste-Viktoria-Krankenhaus.

In 1909, Dr. Kausch described the first successful pancreatoduodenectomy as a two-stage procedure for an ampullary carcinoma.⁶ The first operation, on June 15, 1909, was a biliary diversion procedure as a cholecystoenterostomy. Dr. Kausch shared, “At exploration, I felt a bean-sized lump in the papilla on transduodenal palpation, which obviously was not a gallstone. There was no evidence of metastatic disease. A cholecystojejunostomy was performed. Icterus improves and patient gains weight to the tune of half a kilogram.”

Approximately 2 months later, on August 21, 1909, he undertook the second stage of the operation as a pancreatoduodenectomy followed by reconstruction with a gastrojejunostomy and pancreatoduodenostomy. Dr. Kausch described this procedure: “Adhesions from prior operation add to the difficulty. After Kocherization, I verified resectability. Having confirmed that it was resectable, I went on to fashion a gastroenterostomy, close the pylorus, resect the duodenum and part of the pancreatic head, which was the size of a walnut, ligate the choledochus, suture the cut end of the duodenum to the pancreas.”

The significance of Dr. Kausch’s procedure was largely lost on surgical nomenclature, though some have advocated for the name “Whipple-Kausch” procedure to be included in the eponym.

Dr. Whipple: A Pancreatic Pioneer

“The surgery of the pancreas had been more or less an unexplored field so far as the tumors of that organ were concerned. The very recent recognition of tumors of the islet cells of the pancreas, which gave a clinical picture identical to that caused by an overdose of insulin by the islet cells of these tumors—had intrigued me greatly,” said Dr. Whipple.

Dr. Whipple is one of the 20th century’s major innovators in pancreatic surgery. He was born in Oromia, Persia in 1881, as his parents were serving as American Bible Society missionaries. His family had American roots, with a connection to William Whipple (1730–1785), who was a signer of the US Declaration of Independence. Dr. Whipple’s middle name, “Oldfather,” was the last name of his parents’ close family friends while living in Persia (and is a frequent surgical trivia question for surgical residents in the OR).

As a child, Dr. Whipple spoke fluent English, French, Armenian, Syrian, Turkish, and Persian. In 1896, he moved to Duluth, Minnesota, where he completed his high school education. He attended Princeton University in New Jersey from 1900 to 1904 and spent his junior summer observing in the surgical clinic of David Graham, MD, FACS, in Evanston, Illinois.

Dr. Graham was the father of Evarts A. Graham, MD, FACS, a fellow Princeton alumnus who was studying at Rush Medical College in Chicago, Illinois. Dr. Evarts Graham would later serve as ACS President (1940–1941) and chair of surgery at Washington University in St. Louis, Missouri (1919–1951). He also was a founding member of the American Board of Surgery and performed the first pneumonectomy for carcinoma of the lung. Dr. Evarts Graham also was the first to statistically prove the increased risk of lung cancer in cigarette smokers.

Dr. Whipple attended medical school at Columbia University in New York from 1904 to 1908, and he completed his surgical residency at New York Presbyterian Hospital from 1909 to 1915. He served as chair of surgery at Columbia from 1921 to 1946 and was the first to offer Charles Drew, MD, a pioneering surgeon and researcher, a position in academic surgery.

The field of pancreatic surgery began as a curative treatment for insulin-secreting tumors of the pancreas. Unlike other pancreatic tumors, “insulinomas” represented a targetable pathology, as the diagnosis was straightforward, predictable, did not rely on radiography or physical examination, and was a new indication for abdominal operations.

The insulin molecule and its function were first discovered by Nobel Prize winners Frederick Banting, MD, and Charles Best in Toronto in 1922. In October 1926, William J. Mayo, MD, FACS, who served as ACS President from 1917 to 1920, performed a total pancreatectomy for an insulin-secreting carcinoma. The patient was a surgeon who was affected by profound hypoglycemia, and he initially was treated with continuous duodenal dextrose feedings.

The patient tolerated the procedure well but had persistent postoperative hypoglycemia that was found to be metastatic insulinoma to the liver and kidneys; the patient died in January 1927. In 1929, Roscoe Graham, MD, performed the first surgical excision of a pancreatic insulinoma in Toronto.⁷

From 1933 to 1935, Dr. Whipple reported his case series on insulinoma resections of eight tumors in six patients. He described a typical and essential triad:

1. An attack of nervous or gastrointestinal disturbances appearing in the fasting state
2. Associated hypoglycemia (with readings below 50 mg/dl)
3. Relief occurring immediately by ingestion of glucose

Without this triad of symptoms, Dr. Whipple argued that the patient should not be considered a candidate for an operation.

In 1935, Dr. Whipple presented the first reported cases of pancreatoduodenectomy with compete duodenal excision as a two-stage procedure among three patients at an American Surgical Association meeting.⁸ The first patient died within 30 hours postoperatively from anastomotic breakdown, the second patient died at 9 months postoperatively from cholangitis, and the third patient died at 24 months from liver metastases.

The discussants for Dr. Whipple’s presentation were Damon Pfeiffer, MD, FACS, and Dr. Evarts Graham, who stated: “It is very fitting, however, that the Society should recognize the importance of this contribution because it is quite apparent that a new and brilliant chapter is being added to the surgery of this condition. None of us is too young to be aware of the timidity with which surgeons in general have approached any radical interference on the pancreas.”

On March 8, 1940, Dr. Whipple performed the first one-stage pancreatoduodenectomy.⁹ In spring 1940, a group of European surgeons was visiting surgical clinics in the US, and Dr. Whipple hosted the group, affording them the opportunity to watch him perform an operation from the amphitheater.¹⁰

The patient was a 53-year-old woman with a preoperative diagnosis of a gastric antral mass. Only after the stomach was divided (without opening lesser sac), Dr. Whipple was “astonished and chagrined” to discover that the tumor was located in the head of pancreas.¹¹ The planned distal gastrectomy was converted to one-stage pancreatoduodenectomy with antecolic gastrojejunostomy and choledochojejunostomy (as the gallbladder had been previously removed).

Dr. Whipple did not perform a pancreatojejunostomy but rather tied off the pancreatic duct. The patient did well, and the pathology on the specimen, appropriately for Dr. Whipple’s career, demonstrated a non-functioning islet cell carcinoma.⁹

As a result of this operation, he advocated for the one-stage procedure due to its three primary benefits:

1. The advent of vitamin K (which first became commercially available in 1939) meant that biliary diversion was no longer required for coagulopathy correction.
2. This approach avoided adhesion formation from repeat operation.
3. A choledochojejunostomy avoided the pitfalls of a cholecystoenterostomy.

Dr. Whipple would go on to perform 37 pancreatoduodenectomies in his career, including 30 for cancer. In 1941, Verne Hunt, MD, FACS, from the University of California, Los Angeles, described the pancreatoduodenectomy and completed the first planned one-stage Whipple operation that we know today.⁴

In 1942, Dr. Whipple began performing duct-to-mucosa pancreaticojejunal anastomoses to his procedures. Later, he described steps in his operative approach:¹¹

• At least 2 days of vitamin K and bile salts therapy.
• The distal half of the stomach, the entire duodenum, the terminal portion of the common duct, and the head of the pancreas were removed en masse.
• Vertical limb of the jejunum, starting at the duodenojejunal junction, was brought up through a rent in the mesocolon, behind the colon, with the following anastomoses in sequence:
  • Choledochojejunostomy, end to end.
  • Anastomosis between the pancreatic duct and the wall of the jejunal opening the size of the pancreatic duct, followed by the tacking of the stump of the resected pancreas to the wall of the jejunum.
  • End-to-side gastrojejunostomy. A sump drain in the bed of the duodenum was used. Silk technic was employed throughout.

Dr. Whipple’s Later Career

Dr. Whipple’s professional trajectory was highlighted by further revolutionary surgical innovations. In collaboration with Arthur Blakemore, MD, Dr. Whipple developed the portocaval shunt procedure for portal hypertension in 1945,¹² and he performed 60 portocaval shunts by his retirement.⁹

During World War II, he was appointed to the medical committee of the National Research Council and chaired the Committee on Burns and Contaminated Wounds. Dr. Whipple studied the use of penicillin as a safe antibiotic for treating various infections and the “second set” immune phenomenon (now known as sensitized/memory immune response) for skin grafts in the Glasgow Royal Infirmary Burn Unit.

Dr. Whipple also served as a consulting surgeon for the North African campaigns along with Edward D. Churchill, MD, FACS, from Massachusetts General Hospital in Boston. After the war, Dr. Whipple was the clinical director of the Memorial Hospital in New York (now Memorial Sloan Kettering Cancer Center) and served as a trustee of Princeton University and the American University in Beirut from 1941 to 1963.

Modern surgeons have continued to refine these techniques and expedite perioperative care for their patients. Charles Garner Child III, MD, FACS (1908–1991), reported the first pancreatoduodenectomy with en-bloc portal vein resection in 1952, which expanded the scope of resectability in pancreatic tumors.¹³

With regard to further improvements in pancreatojejunostomy technique, Richard Cattell, MD, FACS (1900–1964), and Kenneth Warren, MD (1911–2001), first described their eponymous two-layer pancreatojejunostomy in 1953.¹⁴ Leslie Blumgart, MD, FACS (1931–2022), and David Kooby, MD, FACS, reported the eponymous Blumgart pancreatojejunostomy anastomosis in the Journal of the American College of Surgeons in 2010.¹⁵

Pancreatic surgery has a rich and colorful history and includes contributions from several trailblazing surgical leaders. The legacy of the pancreatoduodenectomy demonstrates the application of centuries of dedicated anatomical, pathologic, and surgical study to produce an elegant operation to treat diseases of the pancreas.

Dr. Brendan Lovasik is a clinical fellow in transplant surgery at Washington University in St. Louis, Missouri.

References

1. Busnardo AC, DiDio LJ, Tidrick RT, Thomford NR. History of the pancreas. Am J Surg. 1983;146(5):539-550.
2. Tsuchiya R, Kuroki T, Eguchi S. The pancreas from Aristotle to Galen. Pancreatology. 2015;15(1):2-7.
3. Schnelldorfer T, Adams DB, Warshaw AL, Lillemoe KD, Sarr MG. Forgotten pioneers of pancreatic surgery: Beyond the favorite few. Ann Surg. 2008;247(1):191-202.
4. Are C, Dhir M, Ravipati L. History of pancreaticoduodenectomy: Early misconceptions, initial milestones and the pioneers. HPB (Oxford). 2011;13(6):377-384.
5. Halsted WS. Contributions to the surgery of the bile passages, especially of the common bile-duct. Boston Med Surg J. 1899;(141):645–654.
6. Kausch W. Das Carcinom der Papilla duodeni und seine radikale Entfernung. 1912;78:439-486.
7. Piper CC, Yeo CJ, Cowan SW. Roscoe Reid Graham (1890 to 1948): A Canadian pioneer in general surgery. Am Surg. 2014;80(5):431-433.
8. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of Vater. Ann Surg. 1935;102(4):763-779.
9. Whipple AO. Pancreaticoduodenectomy for islet carcinoma: A 5-year follow-up. Ann Surg. 1945;121(6):847-852.
10. History of Medicine: Whipple’s Improvised Breakthrough. Columbia University. Available at: https://columbiasurgery.org/news/2015/11/12/history-medicine-whipples-improvised-breakthrough. Accessed April 3, 2025.
11. Whipple AO. A reminiscence: Pancreaticduodenectomy. Rev Surg. 1963;20:221-225.
12. Blakemore AH. Portacaval anastomosis for portal hypertension. Surgery. 1949;26(1):99-102.
13. Child CG 3rd, Holswade GR, McClure RD Jr., Gore AL, O'Neill EA. Pancreaticoduodenectomy with resection of the portal vein in the Macaca mulatta monkey and in man. Surg Gynecol Obstet. 1952;94(1):31-45.
14. Warren KW, Cattell RB. Basic techniques in pancreatic surgery. Surg Clin North Am. 1956;36(3):707-724.
15. Grobmyer SR, Kooby D, Blumgart LH, Hochwald SN. Novel pancreaticojejunostomy with a low rate of anastomotic failure-related complications. J Am Coll Surg. 2010;210(1):54-59.