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1 Historical background
Although cancer is described in ancient manuscripts, it is only in the last 150 years that there has been clear recognition of the nature of the disease. At the end of the eighteenth century, cancer was widely believed to be contagious; not until the early twentieth century did clear evidence begin to emerge that cancer, while not itself infectious, may be caused by infectious organisms. As we enter the twenty-first century, there is sufficient understanding of infection-associated cancer to allow ambitious prophylaxis schemes to be undertaken.
Antiquity of cancer
It is probable that cancer has existed for hundreds of millions of years, since the emergence of the first complex multicellular organisms. In a multicelled organism it is vital for cell growth and division to be tightly regulated; indeed cancer can be defined as a breakdown of the regulation of cell growth, division and death. There are reliable descriptions of malignant tumours in modern invertebrates, implying that cancer antedated the emergence of vertebrates.
In fossilized bones, in contrast, it is often possible to delineate very fine details of internal structure and, in some cases, evidence of erosion caused by soft tissue swellings; some bones show changes consistent with specific cancers, or bone metastases1. There is a general consensus that there is physical evidence of malignant disease in dinosaurs. Fossilized remains of a caterpillar from over 20 million years ago have been found to contain tumours which may have been caused by viral infection2.
Plant tumours such as crown galls have been compared with animal cancers3,4; it has been known for a century that one of the commonest causes of such growths is a bacterial infection -Agrobacterium tumefaciens5.
The Kanam mandible
The Kanam mandible is a jawbone fragment from an early hominid, who is estimated to have lived between 500 000 and 1 million years ago; it was discovered by Louis Leakey in Kenya in the 1930s6. The inner surface of the jawbone bears a tumour mass often cited as the oldest example of a human cancer. Some have suggested it to be an osteogenic sarcoma, others consider it to be a Burkitt lymphoma (BL)7 (a tumour associated in sub-Saharan Africa with Epstein-Barr virus infection). Unfortunately however a recent re-examination using sophisticated technology concluded that'ā¦both macro and microanatomy are consistent with bone pathology secondary to fracture'8. It would seem that the unfortunate owner of the Kanam mandible suffered not cancer but a broken jaw. There is no obvious candidate to replace the Kanam mandible as the oldest known hominid cancer. Many prehistoric bony remains bear probable tumours but none has an unequivocal hallmark of cancer. Stathopoulos, in a book chapter on 'Bone tumours in antiquity'9 lists many of these. Newby and Howard state 'The oldest specimen of a human cancer was found in a female skull dating from the Bronze Age (1900-1600 BCE)'10; unfortunately they give no source to support this assertion.
The cancer papyruses
The oldest written descriptions of cancer are found in Egyptian papyruses which date to around 1500 BCE and are based on tracts from around 2500 BCE. Many elements of the papyri are difficult to interpret, due to changed terminology and disease concepts. The Edwin Smith papyrus describes surgical cases; at least one case seems to be a cancer (of the breast)11. The papyruses are purely case histories with no speculation as to causes of cancer. It is probable that, like other natural phenomena in the prescience era, they attributed development of cancer to supernatural causes.
Graeco-Roman literature
Hippocrates (460-375 BCE) is credited with the first use of the term cancer (Gk crab)12; possibly because the growths reminded him of a moving crab. He used the terms 'carcinos (a tumor), carcinoma (a malignant tumor) and cancer (a non-healing malignant ulcer)'13. Hippocrates believed that severe, incurable and ulcerated cancers arose from an excess of black bile, while thin bile was responsible for non-ulcerated, curable cancers.
The first specific text on tumours was Galenās 'De Tumoribus Praeter Naturam' (Tumours contrary to nature)14 written almost 2000 years ago. To Galen, tumours meant all swellings, including conditions such as dropsy and even obesity. He embraced the Hippocratic 'humoral' theory of the nature of disease, including cancer - unfortunately for the next 1500 years no one successfully challenged anything written by Galen. In 1543, Vesalius, Professor of Anatomy at Padua, was the first to seriously challenge Galenās errors on anatomy15 ushering in a new understanding of anatomy; unfortunately Galenās humoral theory of disease continued to hold sway. Vesalius also 'wrestled with the knotty problem of clinical differentiation of tumours'16. Physicians in the late sixteenth century did not differentiate clearly between neoplastic growths and other forms of swelling, thus BenoĆ®t (translated by Hunton) wrote, 'Every Cancer almost is uncurable, or hardly cured, sith it is indeede a particular and worst kind of Leprosie'17.
Humours, tumours and cell theories
In 1700, Deshaies Gendron published a closely reasoned argument that cancers were not 'inflammatory masses composed of fluted humours' but rather solid structures composed of body tissues and capable of destructive growth18. In clear contradiction of Galenās teachings, he based this on 'clinical studies and observations of cancerous materials'19. Sadly, the dead hand of Galen lay heavy and Gendronās work was rejected and lay forgotten for many years. It was to be more than a century before medicine emphatically discarded the humoral theory.
At the end of the eighteenth century, cancer was widely thought to be an infectious disease; because of which the first cancer hospital in France (opened in 1779) was forced to move from the city. This was largely influenced by two seventeenth-century clinicians, who argued from analogy to other 'tumours' such as leprosy and elephantiasis - both of which are transmissible16. Beckett, writing in 1712, explicitly rejected the analogy between cancer and elephantiasis, declaring that 'tho' a Cancer has some similitude to an Elephantiasis, they are different Diseases'20.
Cancer patients continued to be refused admission to many hospitals as late as the mid-nineteenth century. Records of the Womenās Hospital in New York show that the Board of Lady Supervisors refused admission of cancer patients to the hospital 'pavilions' - clearly due to a belief that all growths, including cancer, were contagious. The surgeon Marion Sims challenged the Board head-on and continued to admit, and operate upon, patients with early stage cancer. Unfortunately, the result was Simsās dismissal; he went on to become President of the American Medical Association21, so this contretemps clearly did not permanently blight his career.
Reports of 'cancer houses' persisted into the twentieth century and there are still many people who fear that cancer itself is infectious. Alternative explanations exist for multiple cases at a given address; familial cancers may have affected several related occupants of the same dwelling, there may have been shared exposures to environmental carcinogens or there may have been transmission within families of organisms like Helicobacter pylori which are known to increase cancer risk.
At the commencement of the nineteenth century with the flourishing of scientific medicine there was a great deal of interest in the nature, causes and treatment of cancer. In 1800/1801, French anatomist Marie FranƧois Xavier Bichat 'laid down the principles that all tissue was similar in structure, that each type of tissue was a unit of life capable of reproducing itself, and that tumours, cicatrices (scars) and cysts were not inflammations but an overgrowth of cellular tissue'19; like Gendron, Bichat appears to have been far ahead of his time; it was to be more than 50 years before Virchow published his famous axiom 'omnis cellula e cellula' - all cells arise from existing cells22.
In 1802, in London, a group of prominent physicians and lay people formed the "Institution for Investigating the Nature and Cure of Cancer"23. They formulated a list of 13 key questions, most of which are as relevant today as when they were formulated two centuries ago:
(1) What are the diagnostic signs of cancer?
(2) Does any alteration take place in the structure of a part, preceding that more obvious change which is called cancer? If there does, what is the nature of that alteration?
(3) Is cancer always an original and primary disease, or may other diseases degenerate into cancer?
(4) Are there any proofs of cancer being a hereditary disease?
(5) Are there any proofs of cancer being a contagious disease?
(6) Is there any well-marked relation between cancer and other diseases? If there be, what are those diseases to which it bears the nearest resemblance, in its origin, progress and termination?
(7) May cancer be regarded at any period, or under any circumstances, merely as a local disease? Or, does the existence of cancer in one part, afford a presumption, that there is a tendency to a similar morbid alteration in other parts of the animal system?
(8) Has climate, or local situation, any influence in rendering the human constitution more or less liable to cancer, under any form, or in any part?
(9) Is there a particular temperament of body more liable to be affected with cancer than others? And if there be, what is that temperament?
(10) Are brute creatures subject to any disease, resembling cancer in the human subject?
(11) Is there any period of life absolutely exempt from the attack of this disease?
(12) Are the lymphatic glands ever affected primarily in cancer?
(13) Is cancer under any circumstances susceptible of a natural cure?
Theories other than contagion were put forward, perhaps the most prominent being the lymph theory and the blastema theory; the former suggested that cancers arose from local accumulations of lymph, the latter acknowledged that cancers were formed of cells but held that these arose from budding elements, blastema, found between normal cells. Rudolph Virchow argued correctly that all cells (including those in tumours) arise from existing tissues - 'omnis cellula e cellula' and also identified chronic inflammation as a mechanism of carcinogenesis; - one pathway by which infection can lead to malignant transformation. Virchow mistakenly believed that cancers āspread like a liquid'. Thomas Hodgkin, after whom Hodgkin lymphoma is named, recognized that metastasis occurred by spread of elements of the original cancer; 'At the same time, I would by no means deny the possibility, or even probability, that some of the nucleated cells may find their way into the blood, and be arrested at particular parts, giving rise to productions similar to the original tumour, more especially when the latter has advanced to the softening stage, and the lymphatic glands have become affected'24.
From the late 1800s into the early twentieth century, both scientists and lay people believed that cancer could be initiated by ...
