The Case of the Ruthless Ruler With a Deadly Disease

Albert B. Lowenfels, MD; Patrick Maisonneuve, Eng

Disclosures

May 19, 2008

How Was It Possible to Make the Diagnosis so Many Years After the Patient Died?

There was a several hundred-year delay in confirming the diagnosis of bowel cancer that led to the death of Ferrante in the 15th century. After the patient's death, his body was placed in San Domenico Maggiore, a famous Neapolitan church. The extremely dry air and the skillful embalming of the corpse facilitated preservation of the body. About 500 years after Ferrante died, the body was exhumed and an autopsy was performed by a team of specialists from the University of Pisa.[1] At autopsy, DNA samples were obtained from a pelvic mass.[2] It was uncertain whether the pelvic tumor originated in the prostate or colon until the results showed that the mass contained a K-ras mutation, which occurs frequently in colon cancer but is rare in prostate cancer, thus making the colon the more likely source for the tumor (Figure 1).

Malignant tumor discovered in the pelvis of Ferrante I, King of Naples, at autopsy performed several hundred years after his death. From Marchetti-A, Pellegrini S, Bevilacqua-G, Fornaciari-G. K-RAS mutation in the tumour of Ferrante I of Aragon, King of Naples. Lancet. 1996;347:1272. Reprinted with permission.

The patient is believed to represent the earliest known pathologically proven colon cancer. Cancer data have only been collected in an organized manner in the 20th century, so we do not have any reliable information about the frequency of cancer in ancient times. Cancer must have been rare prior to the industrial revolution because most people died before reaching their 50s, after which cancer occurs much more frequently.

What about evidence from mummies? Thousands of mummies have been exhumed, but although bone cancers have been diagnosed, few examinations of mummified bodies have revealed soft tissue cancer. This may be because of the rarity of finding well-preserved, good-quality soft tissue that could used for diagnosis, or more likely, it is because cancer only became a major cause of death in recent times. With the increased use of DNA techniques, we will now have the opportunity to learn more about cancer and other diseases in ancient times.

History of Developments Leading to Current Understanding of Colorectal Cancer Since Ferrante's Death

16th century

  • At this time, based on ideas traceable to Galen, all cancer is thought to be caused by an excess of black bile.

  • Initial advances in anatomy and physiology during this century will eventually lead to the development of surgical techniques for colorectal cancer.

17th century

  • William Vaughan recommends consuming food items that would now be considered part of the healthy Mediterranean diet.[3]

  • In 1630, an English couple with an inherited colon cancer mutation migrated to the United States, where the defect will become widespread, affecting many Americans with attenuated forms of familial adenomatous polyposis.[4]

18th century

  • In 1710, Alexis Littre, after seeing an autopsy on a baby with anal atresia, concludes that a colostomy might have been life-saving. In 1793, for the first time, a colostomy was successfully performed to treat this congenital anomaly.

  • In 1732 the first colectomy is performed for large bowel trapped in a sliding, incarcerated scrotal hernia. The bowel was not resutured.[5]

  • In the1750s, John Wesley, the founder of Methodism, recommends holding a live puppy against the abdomen as a treatment for intestinal obstruction.[6] It is unlikely that this treatment did any good, but neither was it likely to cause any harm. (It should be noted that Wesley did not invent this treatment but was just passing the recommendation along.[7])

  • In the 1760s John Hunter (1728-1793), the famous Scottish surgeon, suggests that if a tumor has spread to the nearby tissue and is still moveable, "there is no impropriety in removing it."[8]

  • In, 1761, Giovanni Battista Morgagni performs autopsies linking actual findings with the patient's symptoms.[9] More than 250 years after Ferrante's death, cancer can now be diagnosed, but only after the patient has died.

19th century

  • In 1826, Lisfranc is the first to report treating rectal cancer treated with peritoneal excision. This procedure, however, leads to a high recurrence rate.[10]

  • In1839, Jean Zulema Amussat performs the first colostomy for obstructing carcinoma of the rectum.[11]

20th century

  • In 1907 Miles performs an abdominoperineal procedure for rectal cancer.[12]

  • In 1932 Cuthberg Duke develops a classification system still used to stage colorectal tumors.

  • In 1960, the American Board of Proctology becomes the American Board of Colon and Rectal Surgery, greatly enlarging the scope of this surgical specialty.

  • In 1964 commercially developed surgical stapling devices simplify bowel anastomoses.

  • In the 1970s the colorectal polyp-cancer hypothesis is developed.[13]

  • In 1969 the first complete colonoscopy is performed.

  • In 1990 Fearon and Vogelstein describe a genetic model for development of bowel cancer.[14]

  • In 1990 the first laparoscopic colectomy is performed.[15]

  • In 1991 the APC gene is discovered.

21st century

  • Cancer of the colon is now the third leading cause of death in the United States, affecting more than 150,000 persons and causing 52,000 deaths.

  • There is widespread use of laparoscopic colectomy.

  • The use of genetic markers for screening and prognosis has increased.

  • There is increased use of anastomotic procedures rather than abdominoperineal resection for rectal cancers.

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