Introduction
The patient was an elderly male, a member of a prominent royal family, who became a ruthless ruler of a European principality. Little is known about his medical background, family history, or details about his final illness except that he was obese and a nonsmoker. From what is now known about his cause of death, it is likely that disturbing symptoms would have appeared several months before his terminal illness and would have included abdominal pain, constipation accompanied by vomiting, and weight loss. He probably would have noted blood in his stool. He did not undergo any diagnostic procedures nor did he undergo any operations. During his reign, he was feared as a ruthless but energetic king, ruling over a large geographic area. He survived several life-threatening attacks by conspirators. There may also have been attempts to poison him. To the great relief of his subjects, he died at age 63 after ruling for 36 years. Several hundred years after his death, the patient’s body was exhumed so that an autopsy could be performed. It revealed a definitive pathologic diagnosis for his final illness.
1. What diagnosis do you think best explains the presumed symptoms?
A) Biliary tract cancer
B) Diverticulitis
C) Poisoning
D) Abdominal aneurysm
E) Colorectal cancer
2. Who was the patient?
A) Alexander the Great
B) Ferdinand I of Naples
C) Peter the Great
D) Napoleon
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
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.
How Would Ferrante Be Treated Today?
Screening for Colorectal Cancer
As a monarch, Ferrante would have received the best treatment. He was at average risk of developing cancer, and today he would have several acceptable screening methods for colorectal cancer available to him, including colonoscopy beginning at age 50 and every 10 years thereafter. Colonoscopy would have revealed the lesion at a resectable, presumably curable stage.
Colonoscopy began to replace the far less effective sigmoidoscopy in 1969, when new optically sophisticated endoscopes became available that made visualization of the entire colon feasible. Several reviews support the concept that screening for colorectal cancer is beneficial, with an estimated cost of $10,000 to $25,000 per year of life saved. Although it is still uncertain whether colonoscopy is the best preventive strategy, the risk for colorectal cancer is less than 1% five years after a negative colonoscopy, and the procedure has become accepted as an effective screening tool.[16-19] President Reagan had undergone diagnostic but not screening colonoscopy in 1985 prior to his surgery for right-sided colon cancer. In contrast, President George W. Bush has already undergone several colonoscopies for the removal of benign polyps.
During 2002, endoscopists performed more than 14 million colonoscopies in the United States, allowing for a fast, accurate, reliable diagnosis of bowel cancer, which may be one of the factors responsible for the steady decrease in the incidence of colorectal cancer
Treatment of Ferrante’s Colorectal Cancer
Undoubtedly Ferrante would have had full insurance coverage and sought care at a recognized institution skilled in the diagnosis and management of colorectal cancer. This would have improved his chances of survival because, as pointed out in several studies, differences in survival in colorectal cancer are related to income and/or socioeconomic status.[20,21] Today it is likely that Ferrante would have had a laparoscopic surgical bowel excision, given that recent studies appear to show outcomes similar to those of conventional open colectomy.[22-25] The decision for adjuvant therapy would depend on the stage of disease and the molecular characteristics of the excised tumor. Presuming that the tumor was detected before spreading, his expected 5-year survival would be about 60% to 70%.
Brief Biography
Don Ferrante was born in Spain, the illegitimate son of Alfonso V of Aragon. At the age of 35, in 1458, he inherited the kingdom of Naples from his father. At that time, it had the most powerful navy in the western part of the Mediterranean. During his reign the kingdom was under steady attack not only from external powers such as the Turks, the French, the Republic of Venice, and the Papacy, but also by the local barons. He had 2 wives, 3 mistresses, and several legitimate and illegitimate children
Ferrante was known as a politically adept but completely ruthless, evil king. He maintained power by treachery — often imprisoning and executing his enemies. As an example of his antisocial character, on one occasion he invited many of his enemies to a banquet supposedly to celebrate a peace agreement. However, at the banquet’s conclusion, many of the guests were gruesomely murdered. Some were fed to the crocodiles that guarded the castle’s moat. The bodies of others were mummified so that Ferrante could display the corpses dressed in their usual costumes in the local dungeon. Even during Ferrante’s time, such disrespectful treatment of one’s enemies was considered unacceptable.
What is known about Ferrante’s other family members?
Ferrante had numerous relatives, but little is known about their health status. No relative is known or suspected to have died from colorectal cancer. Perhaps his most well-known relative is his granddaughter Isabella of Aragon (1470-1524), also known as the Duchess of Milan. Until 2008 the Duchess of Milan was widely believed to have been the model for Leonardo Da Vinci’s Mona Lisa — possibly the world”s most famous painting. Leonardo was court painter for the Duke of Milan, and some of the details of Mona Lisa’s dress suggest the sitter could have been the Duchess of Milan. In addition, there is a Raphael painting of the Duchess that resembles the Mona Lisa. More recent discoveries dispute this. The current view is that Lisa Gherardini, or Lisa Giocondo (1479-1551), wife of a wealthy Florentine businessman, Francesco del Giocondo, is the true woman whose enigmatic smile is now such a familiar image.
Summary
The death of Ferrante in 1494 is now known to have been caused by large bowel cancer. The diagnosis was delayed for several hundred years and only became apparent at the end of the 20th century when DNA analysis revealed k-ras mutations within a tumor mass compatible with colorectal cancer. This histologically confirmed case of large bowel cancer occurring during the Renaissance is unique because there is a scarcity of well-preserved tissue dating back that far that is suitable for diagnostic studies.
We are unable to make any reliable estimates of the frequency of colorectal cancer prior to the 20th century. However, today it is the third most common cancer in the United States, and on a global basis, it causes an estimated 510,000 deaths annually.
The 20th century has seen remarkable advances in our understanding of this cancer, particularly the mutations that characterize the transformation from normal colonic mucosa to adenomas and eventually to malignant disease. Just as important has been the development and increased utilization of colonoscopy as both a screening and therapeutic tool. Future advances may include new diagnostic screening tools, including computed tomography colonography and new surgical approaches such as robotic surgery and natural orifice transluminal endoscopic surgery (NOTES).
In the 15th century, when Ferrante had bowel cancer, the disease could be neither diagnosed nor treated: if he were alive today, his lesion could be treated effectively. Rather than enduring a painful death, he would likely be a survivor, able to enjoy watching or perhaps even participating in daily Italian politics.
Reviewed by Dr. Ramaz Mitaishvili
Glendale, CA
