http://www.nature.com/ncpgasthep/journa ... p0684.html
Nature Clinical Practice Gastroenterology & Hepatology (2007) 4, 52-57
doi:10.1038/ncpgasthep0684
Received 12 May 2006 | Accepted 15 September 2006
Napoleon Bonaparte's gastric cancer: a clinicopathologic approach to staging, pathogenesis, and etiology
Alessandro Lugli, Inti Zlobec, Gad Singer, Andrea Kopp Lugli, Luigi M Terracciano and Robert M Genta* About the authors
Correspondence *Pathology & Laboratory Service–113, VA North Texas Health Care System, 4500 S Lancaster Road, Dallas, TX 75216, USA
Summary
Background Numerous hypotheses on the cause of Napoleon Bonaparte's death have been proposed, including hereditary gastric cancer, arsenic poisoning, and inappropriate medical treatment. We aimed to determine the etiology and pathogenesis of Napoleon's illness by a comparison of historical information with current clinicopathologic knowledge.
Investigations Evaluation of Napoleon's clinical history, original autopsy reports, and of historical documents. The clinicopathologic data from 135 gastric cancer patients were used for comparison with the data available on Napoleon.
Diagnosis At least T3N1M0 (stage IIIA) gastric cancer. Napoleon's tumor extended from the cardia to the pylorus (>10 cm) without infiltration of adjacent structures, which provides strong evidence for at least stage T3. The N1 stage was determined by the presence of several enlarged and hardened regional (perigastric) lymph nodes, and the M0 stage by the absence of distant metastasis. Analysis of the available historical documents indicates that Napoleon's main risk factor might have been Helicobacter pylori infection rather than a familial predisposition.
Conclusions Our analysis suggests that Napoleon's illness was a sporadic gastric carcinoma of advanced stage. Patients with such tumors have a notoriously poor prognosis.
Keywords: gastric cancer, Helicobacter pylori infection, hereditary gastric cancer syndrome, Napoleon Bonaparte, TNM stage
Top of pageThe case of napoleon bonaparte
Napoleon Bonaparte died on 5 May 1821, 6 years after his arrival at the South Atlantic island of St Helena where he had been sent into perpetual exile by the British. The Emperor's death, made increasingly mysterious by the remoteness of the location where it occurred, has enthralled historians for years.
The autopsy reports, prepared by his personal physician Dr Francesco Antommarchi and the English physicians present at the time of the autopsy, indicate that gastric cancer was the cause of death.1, 2, 3 Sokoloff's medicohistorical study published in 1938 suggested that Napoleon's father (Charles Bonaparte) died of stomach cancer and, therefore, Napoleon could have had a familial predisposition for gastric cancer and could have suffered from a hereditary disease.4 In 1961, an elevated arsenic concentration was found in Napoleon's hair and inspired fanciful conspiracy theories as well as some plausible hypotheses of arsenic poisoning; most of these theories have now been largely discredited, yet not completely abandoned.5, 6 Not surprisingly, inappropriate medical treatment, such as a tartar emetic, calomel (mercurous chloride) and a decoction of bark, has also been suggested as the cause of Napoleon's illness;7 however, the wisdom of ignoring the historical perspective and applying modern knowledge to disparage old treatments must be questioned.
Napoleon's reported obesity at the time of his death is the evidence most frequently used to counter the argument that gastric cancer caused his death. On the basis of strong circumstantial evidence, however, our group has shown that a weight loss of 10–15 kg occurred in the last 6 months of Napoleon's life.8 The ongoing debate over Napoleon's cause of death, perhaps rekindled by celebrations of the bicentenary of Napoleonic history, is in part sustained by the absence of a histologic examination of Napoleon's stomach lesion.
To test the hypothesis that Napoleon died of gastric cancer we have used a combination of current medical knowledge and historical information (the autopsy reports, the memoirs of his physicians on St Helena [Drs O'Meara,9 Verling,10 Stokoe,11 Arnott12 and Antommarchi1] and the most important eye witnesses on St Helena [De Las Cases,13 Bertrand,14 Gourgaud,15 Montholon,16 Marchand,17 Saint-Denis18 and Balcombe19]). By examination of the available medical histories of Napoleon's family members,20, 21 we have also critically evaluated the validity of Sokoloff's suggestion of familial gastric cancer as the etiology of Napoleon's cancer and propose an alternative explanation.
Clinical history
We studied Napoleon's clinical history according to the proposal of Dr Jean-François Lemaire, a medical doctor, historian and expert in Napoleonic history, who summarized Napoleon's health on St Helena and categorized it into five phases (Table 1).2
Table 1 Clinicopathologic approach to Napoleon's gastric illness on St Helena (1815–1821).
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Phases 1–3 spanned October 1816 to September 1820. In general, Napoleon's health was satisfactory during the first 2 years of this period but in September 1817 and January 1819 he complained of severe epigastric pain, pain in the right scapula, nausea, and headaches. His physicians reported emesis, paleness, and constipation alternating with diarrhea. He experienced sporadic episodes of fever, chills, and jaundice with dark urine, which were indicative of a biliary condition. This condition was later supported by the postmortem finding of biliary sludge, described as a "distended gall bladder containing very thick and lumpy bile".2
In phase 4 (October 1820–February 1821), Napoleon's health deteriorated rapidly. He experienced persistent abdominal pain, emesis, nausea (with aversion to meat), dysphagia, constipation, night sweats, fever, progressive weakness, and weight loss. One of Napoleon's remarks recorded at that time is highly significant: "For me, every activity is a Herculean task."14 Montholon noted in a letter dated 5 December 1820: "The illness of the Emperor has definitively worsened. His pulse is weak, his gums, lips and nails are colourless."22
Phase 5, the 2 months that immediately preceded Napoleon's death (March 1821–May 1821), is well documented in Dr Antommarchi's memoirs: the Emperor suffered from strong, diffuse, abdominal pain (present in 48 of 48 days); fever (present in 36 of 48 days); emesis (present in 32 of 48 days); night sweats (Napoleon had to change clothes several times every night); hematemesis and melena on 5 April 1821; and tachycardia (112 beats per minute) on 1 May 1821.1, 23 Napoleon died 4 days later on 5 May 1821.
The autopsy report
The postmortem examination was performed the day after Napoleon's death (6 May 1821) by Dr Antommarchi, a pupil of Giuseppe Mascagni (1755–1815), a famous anatomy professor at the University of Siena.1, 2 According to Antommarchi's first and second autopsy reports, as well as the findings described by the English physicians,1, 2, 3 the external inspection documented an important amount of weight loss. Napoleon's height was 168 cm and his skin extremely pale. His hands and feet had no pathologic alterations. Internal examinations revealed several 'tuberculous' excavations in the superior lobe of the left lung; the right lung was completely normal. Several bronchial and mediastinal lymph nodes were enlarged and necrotic. In addition, a moderate, bilateral pleural effusion was observed. The heart was very pale, but without pathologic findings.
The stomach was filled with dark material that resembled coffee grounds, a strong indication of upper gastrointestinal bleeding that could have been the immediate cause of death. Examination of the gastric wall revealed an ulcerated lesion with hardened, irregular borders that extended from the cardia to the pyloric region (>10 cm) and a smaller prepyloric ulcer with thick adherences to the liver. The lesser omentum was enlarged and hardened, in contrast to a normal greater omentum. The perigastric lymph nodes were hardened and enlarged and some of them were necrotic. The liver and the spleen were congested. Dark material that resembled coffee grounds was also found in the colon.
The kidneys and the urinary bladder showed no relevant pathologic findings. Other relevant negative findings included the absence of hyperkeratotic lesions in the skin of the hands and feet, normal nails, the absence of other tumors, and "a very pale heart without any hemorrhage".1 In aggregate, these findings militate against the possibility of chronic arsenic poisoning, which is characterized by palmar and solar keratosis, Mee's lines in the fingernails and toenails, cancers of the skin, lung and bladder,24 and subendocardial hemorrhage on the left ventricular wall of the interventricular septum.25 According to Maresch, the absence of subendocardial hemorrhage virtually rules out arsenic poisoning as a cause of death.25 In 2004 it was shown that an elevated arsenic concentration was found in Napoleon's hair in 1814, before his exile to St Helena.26 Other than deliberate poisoning, several possible sources of arsenic intoxication have been proposed in Napoleon's case.27 In addition, historical evidence suggests that this theory of arsenic poisoning is highly unlikely.28 Together, these arguments suggest arsenic poisoning should be excluded as the cause of Napoleon's death.
Top of pageDiscussion of diagnosis
Virtual pathology of the gastric lesions
In the absence of histopathologic confirmation, the diagnosis of Napoleon's gastric cancer must rest primarily on the characteristic morphologic appearance of gastric tumors. Bormann's classification of gastric cancer subdivides tumors into four types: polypoid, fungating, ulcerated, and infiltrative.29 Ulcerated carcinomas can mimic peptic ulcers, but careful examination usually allows a correct diagnosis. Gastric ulcers are usually small, well-circumscribed, punched-out lesions with a clean base and smooth, edematous margins (Figure 1A). By contrast, ulcerated carcinomas have irregular borders, which are firm, fixed, and often raised (Figure 1B); the ulcer crater is typically filled with necrotic and hemorrhagic material29 and careful inspection usually allows the observer to distinguish a malignant from a benign ulcer.30
Figure 1 Macroscopic pictures of gastric lesions.
(A) A benign gastric ulcer, which is a well-circumscribed, punched-out lesion (histologically confirmed). Courtesy of the Archive of the Institute of Pathology, University Hospital Basel, Switzerland. (B) An ulcerated gastric cancer with irregular borders, which are firm, fixed, and often raised (histologically confirmed). Courtesy of the Archive of the Institute of Pathology, Cantonal Hospital Liestal, Switzerland. The macroscopic aspect of the ulcerated gastric cancer is almost identical to the description of Napoleon's gastric lesion made by Dr Antommarchi in his autopsy report.
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As we were obviously unable to observe and palpate Napoleon's gastric lesion directly, we compared the features of Antommarchi's description of an "ulcerated gastric lesion with hardened, irregular borders covering the stomach from the cardia to the pyloric region" with the features of macroscopic images of 50 histologically proven benign ulcers and 50 gastric cancers (representing all four subtypes) obtained from our archives. From this comparison we concluded that the description of Napoleon's lesion was highly consistent with Bormann's type III (ulcerated) gastric cancer.1, 23 According to Dr Lemaire, the small prepyloric ulcer with adherences to the liver described in the autopsy report seems most consistent with a peptic ulcer that might have penetrated through the gastric wall into the liver long before Napoleon's death.2 The clinicopathologic approach to Napoleon's gastric illness on St Helena is summarized in Table 1.
Staging of Napoleon's gastric cancer
After a reasonable level of certainty was reached that the largest gastric lesion represented an ulcerated-type gastric carcinoma, we wanted to determine its tumor-node-metastasis (TNM) stage. To obtain a baseline comparison, we analyzed the relationship between tumor size (greatest diameter), T stage (depth of invasion), and N stage (N0 versus >N0) retrieved from the histopathologic reports of 135 gastric cancer patients, treated in 1986–2003 (age range 17–95 years) whose clinicopathologic data were available from the archives of the Institute of Pathology, University Hospital of Basel, Switzerland.
The association of tumor size with T stage and N stage was evaluated using regression analysis. The relationship of T stage with N stage was assessed using the 2 test and P-values of less than 0.05 were considered to be statistically significant. The mean (with 95% CI limits) for minimum and maximum tumor sizes were obtained for each T and N stage. All analyses were carried out using SAS software (version 9.1, SAS Institute Inc., Cary, NC, USA).
There was a significant association between T stage and tumor size (P <0.0001) (Table 2, Figure 2A). The average size of T2 tumors was 4.7 cm (95% CI 4.1–5.3); T3 tumors were 5.3–7.5 cm in size. Tumors 10 cm in size were most likely to occur in stage T4. Napoleon's tumor extended from the cardia to the pylorus (>10 cm), and was, therefore, likely to be stage T4, although this diagnosis cannot be stated with certainty because no infiltration of adjacent organs was described in the autopsy report.
Figure 2 The association between tumor size and tumor stage in data from surgical resections of 135 gastric cancer patients.
(A) T stage and tumor size. (B) N stage and tumor size.
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Table 2 Association between tumor size, T stage and N stage in 135 gastric cancer patients.
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An association between N stage and tumor size was also observed (P = 0.041) (Table 2, Figure 2B). In addition, a high T stage was correlated with a high N stage (P <0.0001). Lymph node metastases were progressively more frequent in T2 to T4 tumors (P <0.0001); T3 and T4 tumors were more likely to be associated with the presence rather than the absence of lymph node metastases (P = 0.017). According to the autopsy report, there were several hardened and enlarged perigastric lymph nodes, which we believe can be interpreted as metastatic involvement. We view the lymph node status as consistent with at least N1.
Since no distant metastases were described, we assigned an M0 stage. At least T3N1M0 (stage IIIA) should, therefore, be attributed to Napoleon's gastric cancer. Today, the prognosis for stage IIIA gastric cancer, even after curative resection (clearly not an option for Napoleon), is dismal, with less than 50% survival at 1 year and less than 20% survival at 5 years.31, 32, 33
It has been suggested that Antommarchi's second autopsy report could have partially been the result of plagiarism.34 This controversy however, does not influence our investigation since the assessment of T stage relied on Antommarchi's first autopsy report, whereas that of N stage was primarily based on statistical analysis.
Pathogenesis of Napoleon's gastric cancer
The major risk factors for gastric cancer are male sex, chronic gastritis as a result of Helicobacter pylori infection and genetic susceptibility.23, 35, 36 Bile reflux, diet (high in salt, smoked meat and fish, and low in fresh fruit and vegetables), smoking, and alcohol have also been implicated, but it is likely that these factors only increase the risk in H. pylori-infected individuals.37, 38
The presence of an apparently non-neoplastic, penetrating, prepyloric ulcer in Napoleon's stomach is suggestive of a history of chronic H. pylori gastritis, which might have conferred an increased risk of gastric cancer. The risk might have been further increased by his diet, which probably included salt-preserved foods, thoroughly roasted meats, and few fresh fruits and vegetables (standard fare for long military campaigns).
Familial gastric cancer, or at least a familial predisposition for gastric cancer, has been suggested as a possible factor in Napoleon's cancer. This hypothesis is based on the autopsy report of Napoleon's father, Charles Bonaparte, who died at the age of 39 years with a "tumor of semicartilaginous consistency, which was of the shape and size of a large potato or a large elongated pear"2 in the distal part of the stomach. Although this description might correspond to a gastric carcinoma (type I, polypoid), it could also be consistent with a gastrointestinal stromal tumor or, less likely, a lymphoma. Autopsies on other members of the Bonaparte family were not performed and, therefore, the causes of their deaths are only suspected and based on the recorded clinical symptoms or medical reports.2, 19 There is, therefore, no evidence to confirm a hereditary gastric cancer syndrome in Napoleon's family. A general predisposition, perhaps accompanied by a polymorphism in the interleukin 1 gene, which greatly enhances the risk of gastric cancer in H. pylori-infected individuals39 cannot be excluded, but remains in the realm of speculation.
Top of pageConclusions
Napoleon Bonaparte is likely to have had a long-standing H. pylori infection, which might have led to the development of a prepyloric ulcer that created the background for genesis of a gastric adenocarcinoma. A massive gastric hemorrhage that occurred in or around the advanced-stage gastric tumor can be considered to be the immediate cause of his death. This clinicopathologic reconstruction implies that even if the former Emperor had been released or had escaped from St Helena before 1821, his terminal condition would have prevented him from having a further major role in the theater of European history.
Top of pageAcknowledgements
We thank Professor Jeremy Jass, Professor Richard Dirnhofer, and Kristi Baker for their advice on editing this manuscript, and Dr Niels Willi for providing us with macroscopic pictures of gastric ulcers and cancers.
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The authors declared no competing interests.
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