The crab, the turkey and a malignant tale from the year of the rooster†

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 and In to the of for hepatocellular carcinoma — and be the word does off the more — of its and its pathogenesis have been of however, especially for disease, is still hepatocellular carcinoma was still thought to be a disease over years based on the that only had been recorded from the showed that liver cancer is the malignancy in and the in for of all human cancer for and for of whom of are of liver cancer in that are from different in that from in and in and of and to of and in and in and the over the have in this The for liver cancer that is so was already to be recognized in the when of hepatocellular carcinoma were in and other in and 55 that might be and two came to in the in the of a carcinogenic and a the are but one of of secondary by which make up the more than and but many more are the and as probably as a against and as the name are by which are of and especially in The of had been described as early as before the was recognized and but the was There were in the States in the and of a liver in and various fed or and in a in Britain in death of and in in in caused by from the so-called to the and led to the and of the liver was in many other and liver cancer in was found to be to are a of that are as or for their or in and are of and are that and were first from is and is In the were found to be in that is the and has shown to be in and at 8 non-human It did not for the to be between the of by in the and the of liver cell are as human in the on by the of the of the of and and this had also been the of the for on in with that a of of the tumor and in are probably of of hepatocellular And for the rooster. Although the in of hepatocellular carcinoma in is to to be the for primary cancer is especially so in for such as and the approximately million who have or more will develop liver and their are to be by with or before the discovery of an between chronic liver disease caused by and liver cancer was but after the discovery of the to a between liver cancer and because the for the of was more for confirmed its prevalence in primary liver cancer and were in a to who the Nobel Prize in Medicine or for his in the discovery of study on as a for hepatocellular carcinoma was by in was in like the was a of the who only after years as of the of at has had an in the of disease and of A from and a medical he a in medicine from the of in where he had been a medical After a of field study on in and a years back in as a he to in where he for years as a of the Medical had a in while still a at the of Like all the best scientific deep with was a small study of disease from the with to all of the patients he that the of death in that small was liver cancer, a that was not even among the on a of the to for the in the was to a study to liver cancer in and he to so from the of and importance was the of an of liver disease and liver cancer, which suggested that of disease might be in well with the of a study in which he had of from to The of at the was not to the since the idea that a could be responsible for a tumor was not in Peyton Rous with was of and was to from the to out evidence for the of to for his study all of the whose at the where and blood was he over to be over a and was to all the and all causes of that he was not by the of he had to which would have the of and it is a to his and as an that there was virtually no of causes of The patients were to especially since many of had with hepatocellular in when between the States and were only a patients were to but all to the study for not for the a of the did develop hepatocellular carcinoma too, the of a true for liver cancer, which out to be a In of the of primary hepatocellular carcinoma among was only for the cancer and for of the the but only of the among the There can be little that the from this based on an a sound and did as much as before or since to the idea that has a primary in the of liver cell cancer. its it is to this study was so obviously a and not a As might be has many and the Prize in Medicine and the Charles Prize for on Cancer and of him with the Prince for Medicine at the in and he was also by the with the of the for his work on the use of to the spread of in that both and have been recognized as human one might that of the of primary liver cancer has been The of and other of the seem to a of must be for their true in pathogenesis, such as the that the of from patients with hepatocellular carcinoma in is than in healthy and may even with the for patients with hepatocellular carcinoma now is to with lesions that are not for one or to surgical especially liver will as we with a and one that is as as the may not surgical the can be by the Prince from of And had liver in back over the and and we of the patients with liver cancer have a by For this and all other in written the author to the book the A History by and for its of source to the history of The author also for from his in in in with the of in the of hepatocellular The author to his to for and