The crab, the turkey and a malignant tale from the year of the rooster
Authors: Adrian Reuben
Journal: Hepatology (2005)

As when a cancer on the body feeds, And gradual death from limb to limb proceeds; So does the chilness to each vital part, Spread by degrees, and creeps into the heart Thus appears one of the entries under the rubric of cancer, in Samuel Johnson's 1755 dictionary of the English language,1, 2 in which the great lexicographer quotes from Joseph Addison's translation3 of Ovid's Metamorphoses. Although it is by no means certain that Ovid, Addison, Johnson, or even their physicianly contemporaries could really distinguish between cancer, as we know it, and an inflammatory mass, it is certain that true cancer has afflicted living creatures and blighted human flesh since before recorded history began. Indeed, some have conjectured that since cancer is a process of abnormal growth, it must be as ancient as life itself. "Growth for the sake of growth is the ideology of the cancer cell", said Edward Abbey (1927-1989), American writer, maverick, philosopher and environmentalist.4 Traces of tumors have been found in the remains of dinosaurs from the Cretaceous period of the Mesozoic era,5 70 million years ago or more, as well as in Ice-Age bears of the Pleistocene epoch found in European caves, although some have argued that the bears' lesions were simply healing fractures.6 Our human ancestors were susceptible to cancer too, as shown by the presence of a large bony tumor of the femur of Pithecanthropus erectus, dating back half million years or so, which was excavated in Java in 1891 by Eugene Dubois of the Dutch Army Medical Service. Proof of the antiquity of cancer comes from paleo-oncology — the study of carcinomas and sarcomas in ancient human populations and their hominid precursors — which has unearthed malignancy in non-human primates, in bones, skin and soft tissues of mummies from Peru and Chile, as well as in Neolithic skeletons, and Iron and Bronze Age bones, and many others.7, 8 Cancer is alluded to in the cuneiform tablets of the great library of Nineveh and in the Sanskrit documents of ancient India, especially the Sumhita or surgical compendium of the sage and surgeon Susruta, who allegedly flourished nearly 150 years before Hippocrates. And, of course, some of the earliest accounts of human cancer are to be found in the medical papyrii of Ancient Egypt, which is not surprising as bones and skin of mummies from that civilization also showed evidence of neoplasia.7-9 Admittedly, true tumors were not differentiated from inflammatory swellings and chronic ulcerations but they were described, nonetheless, in the Ebers, Smith, and Petrie papyrii, which all date from approximately 1600 BCE.10 Ebers describes 15 growths of various kinds,11 while Smith recommends treatment of non-protuberant breast lesions12 by cauterization with an instrument called the "fire drill". Advocates of Chinese medicine like to argue that the author of the Huang Di Nei Chang, The Yellow Emperor's Medicine Classic, gave the first description of tumors in 2698 BCE.13 But, even if the legendary Yellow Emperor, to whom the book was attributed in veneration, did exist in 2,500-2,700 BCE, in actuality this multi-author work was written much later in history, starting in the late Spring/Autumn and Warring States periods of the Zhou dynasty from 770 to 221 BCE, with revisions taking place up to the Western Han dynasty from 206 BCE to 25 CE.14 It is virtually impossible to narrate the history of Oncology, as it is with many other branches of medicine, without mentioning the names of Hippocrates and Galen sooner or later, especially since the former reputedly coined the term for cancer and the latter popularized it. Everyone remembers that Hippocrates neologized a name for a tumorous growth, i.e., karkinoma15 (καρκι´νωμα) — which we know as carcinoma — from karkinos (καρκι´νoς), the Greek word for crab, which later latinized as cancer entered our language early in the 17th Century alongside variant terms such as canker and chancre, to describe an ulcerated or spreading sore. According to Philemon Holland's 1601 English translation of "The History of the World",16 Pliny the Elder described cancer as "a swelling or sore comming from melancholy bloud, about which the veins appeare of a blacke or swert (dark) colour, spread in the manner of Creifish clees (claws). whereupon it tooke tha name in Latine, like as in Greeke Carcinoma. and such ulcers as in that sort be maintained and fed with thaa humor are called Cancerous, & be untoward to heale, worse commonly for the handling." Yet, irrespective whether the term scirrhus was used for any kind of growth, usually hard, benign or malignant, or carcinoma apertus for soft ulcerated swellings and carcinoma occlusus for a deep-seated one,17 the early analogies of cancer to the crab were graphic and very descriptive.17, 18 According to legend, Galen in the 2nd Century CE and/or Paulus of Ægina in the 7th Century CE thought that the disease was so-called because "… it appears at length with turgid veins shooting out from it, so as to resemble the figure of a crab; or as others say, because like a crab, where once it has got, it is scarce possible to drive it away".18 Incidentally, Hippocrates admonished his colleagues for operating on deep tumors, as so doing might aggravate the disease and hasten the patient's death.19 A prescient caution, perhaps, against surgical resection of liver cancer.20 Galen's contribution to oncology is both astounding and undeniable, to which a catalogue of his work testifies by listing over one hundred references to tumors, and an equal number to cancer as such.21 Like his predecessor by a century or so, Aurelius Cornelius Celsus, Galen attempted to distinguish inflammatory masses, true tumors and other swellings, since the word onkos generally meant any kind of enlargement or growth; and he devoted a small but consequential volume to the task.22, 23 Parenthetically, this work also popularized the four diagnostic characteristics of inflammatory masses, namely "dolor, rubor, calor, and tumor", which had been emphasized by Celsus before him. The importance of this book that is considered by experts to be one of Galen's minor works, however, lies in the fact that its central theme is a concise example of the application of the doctrine of humors to the pathogenesis of disease.22 Galen championed the proposition favored by Hippocrates, that cancer begins in an organ when blood carrying an excess of black bile (melancholia or atra bilis), stagnates within it, especially if the bile is cool.18 Ulceration was thought to depend on the strength of the black bile, so that milder bile caused cancer only. Stronger or "biting" bile attacks the flesh and eats the surrounding skin. The unscathed liver, of course, was the source of the carcinogenic dark humor. Although Galen thought that the outlook of cancer was hopeless, he recommended diet, purgation and blood-letting, as well as his polysubstance concoctions or "galenicals" (especially the universal panaceas Theriac and Mithrodatum24), and obviously avoidance of walnuts. Galen's influence held sway for another 1,500 years until the atrabilious or humoral theory was displaced by the notion that tumors grow from coagulable lymph that seeps out of the blood. In the subsequent history of oncology, which is admirably reviewed18 with related topics on cancer surgery, pathology, epidemiology, virology, pathogenesis, therapy, etc., in a dedicated issue of Seminars in Oncology edited by Carl Kardinal,25 two contributions of the famed 19th Century German pathologist and reformist statesman Rudolph Ludwig Karl Virchow (1821-1902) stand out. First, Virchow harnessed the power of the microscope to make cellular pathology into a scientific system of overwhelming importance. Though his dictum "omnis cellula e cellula" (every cell is derived from a [preexisting] cell) was not entirely his own, his 1858 book on cellular pathology based on physiological and pathological histology26 representing 20 lectures that he gave at the Pathological Institute of Berlin, entirely transformed the science of biology. Therein, Virchow dismissed the idea that cancer arises from amorphous germinal elements that are scattered between normal tissue components, the so-called "Blastema" theory of Müller and Vogel.27 Instead he proposed that chronic irritation in a constitutionally susceptible host causes normal cells to develop into a tumor. Virchow mistakenly thought that this arose from connective tissue elements and not the organ-specific cells themselves. Second, in addition to his scientific prowess and prodigious scholarship, Virchow was an eloquently vocal and frequently provocative opponent of social injustice, an antagonist of pseudoscientific Teutonic racial myths, a proponent of civic enrichment and urban renewal, and a liberal political agitator. His antagonism to Frederich Theodor von Frerichs, the patriarch of modern hepatology, is regretted by hepatologists. His determined, outspoken and unflagging opposition to the militarism of Prussian Prime Minister Prince Otto Edward Leopold von Bismarck, whose honesty he also disputed, goaded the latter into demanding satisfaction in a duel. As the challenged party, Virchow suggested two large sausages as the weapons, one of which was sound while the other was infected with deadly germs (presumably Clostridium botulinum). Virchow offered to eat one if the challenger would eat the other, but His Excellency wisely called off the duel with a burst of laughter. After Virchow, came the Embryonal Theory, the Trauma and Mechanical Isolation Theory, and then the Parasitic Theory. For the latter, Johannes Fibiger's still unconfirmed demonstration that the worm Spiroptera neoplastica induces gastric cancer in rats fed infected cockroaches, erroneously earned him the 1926 Nobel Prize in Medicine and Physiology. Ultimately there was recognition for the discovery by Peyton Rous that chicken sarcoma could not only be transplanted into another fowl28 but that it also could be transferred by injecting a cell-free filtrate of the tumor into a healthy Plymouth Rock hen.29 Notwithstanding, the reader will have to wait a little longer for mention of the turkey and the rooster. Eventually, for his breakthrough, Rous shared the Nobel Prize in 1966, a mere 55 years later,30 with Charles Brenton Huggins31 who pioneered hormonal manipulation therapy for cancer. Compared to the orderly albeit theoretically flawed chronology of neoplasia, the early history of liver cancer can best be described as befuddled. There was confusion because of misunderstandings about the prevalence and nature of the disease, and its tissue of origin, which led to a varying, inconsistent and inexact nomenclature. Aretæus from Cappadocia (the land of fairy chimneys and early Christian settlement, in what is now modern Turkey), a 2nd Century CE contemporary of Galen, got the proceedings off to an auspicious start. The Cappadocian suggested that after there is inflammation, liver swelling changes to a hardened state (possibly cirrhosis) and then settles down to scirrhus, by which he may have meant cancer.32 As with the study of neoplasia in general, the field of liver cancer seems to have lain fallow for 1,500 years, until it was ploughed and seeded again in the 17th Century by the likes of Giovanni Battista Bianchi, Herman Boerhaave, Fredrich Hoffmann and Matthew Baillie, all of whom Frerichs cites as having recognized the disease.33 Although Frerichs commented that the so-called steatomata that Morgagni (who was also a Giovanni Battista) described were metastases from the stomach or pancreas, he does credit Gaspard-Laurent Bayle in Paris with the first accurate description of liver cancer, and for an estimate of its prevalence.33 Coincidentally, it was probably also Bayle who was responsible for the correct use of the term tuberculosis, from which both he and his close friend and hepatophile colleague René-Théophile-Hyacinthe Laënnec, succumbed.34 George Budd estimated that cancer was the commonest organic disease of the liver in the mid-19th Century Britain of his day among patients who had never drunk hard, secondary cancer being more frequent than primary.35 Yet, Frerichs's view that liver cancer largely went unrecognized until the 19th Century prevailed into the 20th Century, especially because the perception that primary liver cancer was far less prevalent than metastatic liver cancer36 was confirmed at a ratio of 25:1.37 Ironically, it was Virchow's aphorism, "that organs commonly affected by metastases are rarely the site of primary neoplasia",38 which greatly delayed the appreciation that primary liver cancer did in fact exist. Hepatologists or, more strictly hepatopathologists, seem to rejoice in using as many different names as possible for the same entity, as we have seen already with stellate cells39 and with what Desmet has called a "Tower of Babel" in the nomenclature of chronic hepatitis.40 For liver cancer, hepatocyte-based tumors have been called cancer trabéculaire,41 adenocarcinoma,42 malignant adenoma,43 carcinoma hepatocellulaire,44 hepatoma45 and ultimately hepatocellular carcinoma, which is now the preferred term. In this connection, the term hepatoma has been applied not only to benign hepatocyte-derived tumors and tumors that are intermediate between benign and malignant, but even to both by no less an eminence than famed American tumor pathologist James Ewing.46 Cancer derived from the bile ducts has been labeled cancer alvéolaire,41 carcinoma cholangiocellulaire,44 cholangioma45 and eventually cholangiocarcinoma. In contrast to the obfuscation of terminology for hepatocellular carcinoma — and truth be told, the word "hepatoma" does trip off the tongue more easily — delineation of its epidemiology and its pathogenesis have been models of clarity these past 50 years.47 Treatment, however, especially for advanced disease, is still wanting. Whereas hepatocellular carcinoma was still thought to be a relatively uncommon disease just over 50 years ago, based on the observation that only 1616 histologically-verified cases had been recorded then,48 estimates from the year 2000 showed that liver cancer is the 5th most common malignancy in men and the 8th in women worldwide, accounting globally for 5.6% of all human cancer (7.5% for men and 3.5% for women), of whom upward of 500,000 (97%) are dying annually.49 Current age-adjusted incidences of liver cancer in men that are available from 24 different geographic regions in 6 continents, show rates that range from 2-4 per 100,000 in Northern Europe, Australia, Israel and India through 13-15/100,000 in Maori New Zealanders, and parts of France and Italy, to values of 22, 28, 36 and 47/100,000, respectively, in Singapore Chinese, Shanghai, Hong Kong and Osaka, Japan.49, 50 Rising incidences in Europe51 and the United States52 over the past decade have heightened parochial interest in this planetary scourge. The geographic predilection for liver cancer that is so evident now53 was already beginning to be recognized in the 1940s, when extraordinarily high rates of hepatocellular carcinoma were noticed in autopsy series and other studies in Asia and southern Africa.54, 55 These epidemiological quirks intimated that environmental carcinogens might be afoot, and two came to light in the 1960s–1970s in the form of a carcinogenic toxin and a virus. Enter first, the turkey. Aflatoxins are but one of several classes of secondary metabolites produced by molds, which make up the more than 400 known mycotoxins. Beneficial mycotoxins include penicillins, cyclosporine and ergot alkaloids but many more are toxic, including the fumonisins, trichothecenes, ochratoxins, sterigmatocystins and zearolenones, as these compounds probably evolved as a chemical defense against insects, microorganisms, nematodes and grazing animals, including humans. Aflatoxins, as the name implies, are produced by Aspergillus flavus (and parasiticus), which are common contaminants of peanuts, soybeans, grains and cassava root, especially in tropical areas. The toxic effects of aflatoxins had been described as early as 1913 before the toxin was recognized and isolated, but the problem was overlooked. There were several outbreaks in the United States in the 1940s and 1950s, of a non-infectious liver disorder in hunting dogs and various livestock fed moldy maize or peanut meal, and in a guinea pig colony in Britain in 1957. Widespread death of turkeys, ducklings, pheasant and partridge occurred in 1960 in Britain, in plague-like numbers, caused by feeding contaminated groundnut (peanut) meal imported from Brazil the previous year. This so-called Turkey "X" disease56, 57 drew attention to the problem and led to the isolation and identification of the toxic culprit. Aflatoxin-induced liver injury was reported too in many other domestic animals, and contaminated cottonseed meal causing liver cancer in farm-raised trout was found to be due to aflatoxin too.58 Aflatoxins are a family of bisfuranocoumarin compounds that are classified as aflatoxins B or G for their blue or green fluorescence, respectively, in ultraviolet light; aflatoxins B2 and G2 are dihydroxy derivatives of B1 and G1, respectively. Aflatoxins M are metabolic products that follow animal ingestion, and were first isolated from milk; aflatoxin M1 is 4-hydroxy aflatoxin B1, and aflatoxin M2 is 4-dihydroxy B2. In the 1960s, aflatoxins were found to be potent carcinogens in animals, particularly aflatoxin B1 that is the most toxic and has shown to be potently hepatocarcinogenic in rodents and at least 8 non-rodent species, including non-human primates.59 It did not take too long for the association to be noticed between the consumption of foods contaminated by fungi in the Third World and the geographic distribution of liver cell cancer.60 Naturally occurring aflatoxins are listed as known human carcinogens in the 11th Report on Carcinogens issued by the National Toxicology Program of the Public Health Service of the U.S. Department of Health and Human Services,61 and this had also been the conclusion recently of the International Agency for Research on Cancer, in 2002.62 Synergism with hepatitis B that involves a specific inactivating mutation of codon 249 of the p53 tumor suppressor gene,63 and genetically-determined individual differences in aflatoxin metabolism are probably codeterminants of risk of hepatocellular carcinoma.63, 64 And now, for the rooster. Although the alarming rise in incidence of hepatocellular carcinoma in developed countries is attributable to hepatitis C,51, 52 hepatitis B continues to be the major risk factor for primary hepatic cancer worldwide. This is especially so in high incidence areas for hepatitis B, such as eastern Asia (excluding Japan) and sub-Saharan Africa.47, 53 Of the approximately 380 million individuals who have hepatitis B virus (HBV) infection,65 25% or more will develop liver cancer,47 and their ranks are likely to be swollen by those with inapparent or "occult" infection.66 Long before the discovery of HBV,67 an association between chronic liver disease caused by infectious hepatitis and liver cancer was suspected68 but unprovable. Soon after the discovery of the Australia antigen, case-controlled studies failed to show a correlation between liver cancer and HBV, because the immunodiffusion assay for the detection of hepatitis B surface antigen (HBsAg) was too insensitive.69 Later, more sensitive techniques for detecting HBsAg confirmed its high prevalence in primary liver cancer patients.70 These and similar retrospective data were important in suggesting a hypothesis. However, according to Baruch S. Blumberg, who won the 1976 Nobel Prize in Medicine or Physiology for his role in the discovery of HBV,67 "the most convincing epidemiological study on hepatitis B as a cause for hepatocellular carcinoma was done by Professor Palmer Beasley, working in Taiwan".71 R. Palmer Beasley's landmark paper72 was published in 1981, which, like the current year, was a "year of the rooster". R. Palmer Beasley (Fig. 1), who only recently retired after 17 years as Dean of the Texas School of Public Health at Houston, has had an abiding career-long interest in the epidemiology of infectious disease and particularly of HBV. A philosophy major from Dartmouth and a Harvard medical graduate, he obtained a Master's degree in preventative medicine from the University of Washington in Seattle, where he had been a medical resident. After a stint of field study on rubella vaccination in Taiwan and a few years back in Seattle as a faculty member, he returned to Taiwan in 1972 where he stayed for 14 years as a member of the U.S. Naval Medical Research Unit (which had a particular interest in infectious disease), while still a faculty member at the University of Washington. Like all the best scientific attachments, Beasley's deep involvement with HBV was somewhat serendipitous. Having inherited a small serum-controlled prospective study of cerebrovascular disease from the 1960s, with access to all of the patients records, he noticed that the leading cause of death in that small cohort was liver cancer, a diagnosis that was not even included among the top 10 on a World Health Organization list of cancers. Having the opportunity to test for the Australia antigen in the stored sera, Beasley was able to design a study to investigate liver cancer in Taiwan, and he obtained funding to do so from the National Institutes of Health (NIH). Of special interest and importance was the novel observation of an apparent familial clustering of liver disease and liver cancer, which suggested that maternal transmission of disease might be operative. This fitted in well with the results of a study in which he had recently participated, showing vertical transmission of HBV from mother to child.72 The reception of Beasley's hepatitis B–cancer hypothesis at the NIH was not enthusiastic, to say the least, since the idea that a virus could be responsible for a solid tumor was not in vogue, Peyton Rous notwithstanding. Foodstuff contamination with aflatoxin was of greater interest and Beasley was "encouraged" to obtain lifetime food histories from the patients, to root out evidence for the ingestion of moldy peanuts, etc. Undaunted, Beasley proceeded to recruit for his study all male civil servants of the government whose jobs afforded them attendance at the Government Employment Clinic, where free annual physical examinations and blood testing was provided. From 1975 onwards, he recruited over 22,000 subjects (22,707, to be precise), over a 3-year period, and was able personally to see all the HBsAg positive individuals, and track all causes of death. Dr. Beasley claims that he was not fazed by the truckloads of punch cards he had to handle, which would have made the rest of us "punch drunk", and it is a testimony to his vim and vigor as an investigator that there was virtually no loss of outcome data, including causes of death. The patients were seemingly pleased to comply, especially since many of them had relatives with hepatocellular carcinoma. Even in 1978, when relations between the United States and Taiwan were strained, only a few patients were temporarily lost to follow up, but all returned to the study later. Fortunately for Beasley (but not for the patients), a few of the HBV-negative individuals did develop hepatocellular carcinoma too, thereby permitting the calculation of a true relative risk for developing liver cancer, which turned out to be a startling 223-fold. In fact, during 75,000 man-years of follow-up the incidence of primary hepatocellular carcinoma among HBsAg carriers was 1158/100,000 versus only 5/100,000 for the controls. Liver cancer and cirrhosis accounted for 54% of the 105 deaths amongst the HBsAg carriers but only 1.5% of the 202 deaths among the non-carriers. There can be little doubt that the findings from this truly landmark epidemiological study, based on an astute observation, a sound hypothesis and dogged perseverance, did as much as anything before or since to support the idea that HBV has a primary role in the etiology of liver cell cancer. By its clarion call, it is easy to understand why this study was so obviously a rooster and not a turkey. Dr. R. Palmer Beasley As might be expected, Dr. Beasley has garnered many prestigious awards and honors, including the King Faisal International Prize in Medicine (1985), and the Charles F. Mott General Motors Prize for Research on Cancer (1987). King Bhumibol and Queen Sikrit of Thailand presented him with the 1999 Prince Mahidol Award for Medicine at the Grand Palace in Bangkok (Fig. 2), and he was also honored by the Taiwan government with the 2000 Health Medal of the First Order, for his pioneering work on the use of hepatitis B vaccine to prevent the spread of hepatitis B infection in Taiwan. Now that both hepatitis B74 and hepatitis C75 have been recognized officially as human carcinogens, one might think that most of the epidemiology of primary liver cancer has been covered. The new epidemic of obesity and other aspects of the metabolic syndrome, seem set to stimulate a new era of epidemiological investigation.76 Similarly, new discoveries must be critically assessed for their true roles in pathogenesis, such as the observation that the median selenium content of toenail clippings from patients with hepatocellular carcinoma in Haimen City, China, is significantly lower than in healthy controls and may even correlate with mortality.77 But perhaps the most pressing challenge facing physicians caring for patients with hepatocellular carcinoma now is how to treat those with lesions that are not amenable, for one reason or another, to surgical extirpation, especially liver transplantation. We will close, as we began, with a poem, and one that is every bit as poignant as Ovid's. While the statistics quoted may not actually reflect surgical outcomes, the sentiments expressed can surely be felt by all. Dean Beasley receiving the Prince Mahidol Award from Queen Sikrit of Thailand (1999). And my beautiful daughter had her liver cut open in Pittsburgh, My god, my god! I rubbed her back over the swollen and wounded essentiality, I massaged her legs, and we talked of death. At the luckiest patients with liver cancer have a 20% chance. (from Pittsburgh by Hayden Carruth78) For this and all other Landmarks in Hepatology written thus far, the author wishes to acknowledge gratefully the book Understanding the Liver, A History by Thomas S. and Peter S. Chen (Greenwood Press, Westport Connecticut 1984) for its wealth of source material pertinent to the history of hepatology. The author also thanks Dr. R. Palmer Basley for sharing recollections from his extensive career in epidemiology and, in particular, in connection with the role of hepatitis B in the etiology of hepatocellular carcinoma. The author continues to express his gratitude to Margie Myers for outstanding literature retrieval and manuscript preparation.