- • Introduction
- • Etiology of Cancer
- • Biology of Cancer
- • Cancer in India—Data Sources and Statistical Relevance
- • Epidemiology of Cancer and Prevention of Cancer in India
- • Screening and Prevention of Cancer
- • Investigations in Cancer
- • Cancer Metastases
- • Carcinoma of Unknown Primary
- • Paraneoplastic Syndromes
The incidences of malignant disease vary with sex, age and geographic locations. Both females and males have almost the same proportion of cancer. The common cancers that affect the women are those of the breast, colon, cervix, ovary, and skin while men are more prone to develop cancer of the lungs, gastrointestinal tract, skin, prostate, oral cavity, pharynx, larynx, bladder and testis. In fact the gap is closing with respect to cancer of the lung in most of the western countries where males and females are equally prone to lung cancer. In fact there is decrease in cancer of the cervix in the west but in India, the problem of cervical cancer is still a serious one. Pediatric cancers are far less than what is seen in adults, but it is growing in importance in terms of mortality. Cancer is the leading cause of death in children up to 14 years, except for accidents, in the developed world. Acute leukemia of both myeloid and lymphatic variety and the solid pediatric tumors of different types like nephroblastoma, retinoblastoma, medulloblastoma, hepatoblastoma and embryonic sarcoma are a few of them. Both Hodgkin’s and non-Hodgkin’s lymphomas develop in male and female patients in equal proportion at any age.
HISTORY OF CANCER
In a historical sense, mention about tumors, particularly about bone and soft tissue tumors, has appeared in the Ramayana, an Indian epic written 2000 years before Christ. References are also available in Susrutha Samhitha (circa 5th BC), a textbook on operative surgery and the surgical removal of tumors. Descriptions about human tumors have appeared in Egyptian papyri (circa1500 BC). In the ancient library in Nineveh in Babylon, in the cuneiform inscriptions, the tumor of the breast is described. Hippocrates of Cos (460-375 BC) coined the word ‘carcinomas’ for malignant tumors and ‘karkinos’ for benign lumps and chronic ulcers. Interestingly, this term ‘cancer’ originated from the Greek word ‘karkinos’ meaning ‘crab’. There is also a Latin word ‘cancrum’ that meaning ‘crab’. There is also a Latin word ‘cancrum’ 4 that means ‘crab’ and it is possible that the word cancer had its origin from the Latin word.
Galen (131-201 AD) wrote about cancer in his prolific writings on medicine. He was also aware of the tumors of the breast and the problem of metastasis and he was the first to coin the word sarcoma (Gr. sarkoma–fleshy growth) under which he included many fleshy tumors. Paul of Aegina (625-690 AD), a well-known Byzantine physician wrote, “Cancer is particularly frequent in the breasts of women.” Hardly any medical or scientific writing was available during the dark ages between the 7th and 17th centuries. The Renaissance, which extended through Europe in the 17th century, brought fresh light on the different facets of medicine including cancer. The invention of microscope by Anton van Leeuwenhoek (1638-1723 AD) and the establishment of histology by Marcello Malpighi (1628-1694 AD) were notable events in the study of cancer. These events led to the discovery by Virchow of the division of cells and from these events, the modern concept of pathology was born.
THE OCCUPATIONAL CANCER
Sir Percival Pott in 1775 incriminated soot, which by its contact on the skin of the scrotum of the chimneysweeps, functions as an etiological factor in the cancer of the scrotal skin, and the concept of occupational cancer became a matter of concern to public health officials. It was found later that these compounds were capable of producing skin cancers in different types of industrial workers. It was noted that workers in Lancaster mills had developed cancer of the abdominal wall skin due to the splash of lubricant oil. In leather industry, the use of isopropyl alcohol is found to be a carcinogenic agent.
In 1884, a German surgeon Rein noticed an outbreak of bladder cancer in workers in the aniline dye industry. It was found that, of the nitrophenols, the dangerous ones are the 2-naphthylamine and 4- dimethylaminoazobenzene. Well-water mixed inadvertently with arsenic was used by people in Taiwan a few decades ago particularly in villages and now a few of them are attending the urology centers with bladder tumors (personal communication). It must not be forgotten that there is usually a lapse of many years between the exposure of a carcinogen and the development of urothelial cancers.
When reports started pouring in from Germany about the urothelial cancers in chemical and dye workers, attention was also drawn to the cluster of workers who developed a peculiar type of lung cancer in the Jochimsthal mines. Bronchogenic cancer of tobacco smokers is yet another example of polycyclic hydrocarbon causing cancer.
More recently, workers in polyvinyl chloride industry have been seen to develop angiosarcoma of the liver and Raynaud-like syndrome due to constant contact with polyvinyl chloride. In India, the chemical industries 5 came into being in the middle of the 20th century but the authors are unable to give statistical data about the etiology of these compounds in the production of cancer.
EXPERIMENTAL CARCINOGENESIS (CHEMICAL AND VIRAL)
Attempts to produce cancer in experimental animals started by the end of the 19th century and the earliest work by Imagiwa and Ichikawa concerning the role of polycyclic hydrocarbon gave conclusive evidence of chemical compounds that induce neoplasm. The original work was done on the skin of the ear of a rabbit, which was painted, with a coal tar product for a few years that ultimately produced skin cancer and their results were published in 1924. The role of polycyclic hydrocarbon has been intensively studied on animals as inducers of neoplasia.
In the case of chemicals that cause cancer, the work of Somervelle in a small Christian hospital, in Kerala, India cannot be forgotten. The incidence of oral cancer, which is high even today, was prevalent among his patients. His inference is that the betel chewing where tobacco and lime (calcium hydroxide) are used initiates mucosal changes in oral mucosa and causes cancer of the oral region.
The role of viruses producing cancer in animal struck the attention of research workers as early as 1910. The experimental work was carried out in rodents and fowls. Ellerman and Bang in 1908, discovered fowl leukemia as the first virus induced tumor. Rous in 1911, Shope in 1932, Lucke in 1934 and Bittner in 1936 are some of the earliest workers in the field. Among them, Rous identified in 1911 a filterable virus producing neoplasm in animals. It was seen that this filterable agent is a virus capable of producing nonlethal mutations in normal stable cells that ultimately develop into a neoplasm. Later this virus was identified as RNA virus. He was awarded the Nobel Prize for this pioneering work on the role of virus in cancer in 1966.
Nigerian and Harris isolated a microorganism, which they thought, was of viral nature from cases of human leukemia but it has been shown that this is in fact a mycoplasma, and its etiological connection with leukemia is very doubtful. The occurrence of patients with leukemia in clusters would support the hypothesis that an infective agent, possibly a virus, was responsible for the initiation of leukemia.
Another important landmark in the study of oncogenic viral tumors is the work of Gross in 1951. He was able to isolate the virus producing leukemia in a mouse and by 1953; he isolated another virus from the cell filtrate that can cause tumors in mice, rats and hamsters. This is polyoma virus, which specifically causes salivary gland tumors in the above-mentioned animals. The research workers in this field accepted the concept that the virus alters the genetic code in the DNA and from a normal cell, a mutated cell that ultimately produces a clone of malignant cell is developed.
THE MOLECULAR BASIS IN CANCER
Even though the scientists knew about the role of virus in animal cancer, they found it difficult to pinpoint the sites at which these changes take place. The pathologists working with a light microscope found that the structure 6 of a malignant cell was different from that of normal cell. Walter Sutton in the year 1903, while an undergraduate student at Columbia University, discovered the chromosomes and its pattern in the cells. It was difficult to evaluate the role of chromosome in certain familial diseases and the search for some other factors in chromosomes that would give an answer to these genetic diseases. Working on these hypotheses, Thomas Morgan and his associates at the Columbia University mapped the position of different genes in the chromosomes for which he was awarded the Nobel Prize for medicine in 1933. In 1934, Bovril suggested that cells become malignant either by the overexpression of genes that promote replication or the inhibition of genes that control cell division.
“What is the mechanism of the perfect replication of cells?”, was a question the scientists wanted an answer to. Is there a code that can be transferred from one cell to its progeny? James Watson and Frances Crick, who identified the structure of DNA, and opened a gate to the new universe of scientific discoveries, provided the answer to this question. This discovery gave the concept of transferring the genetic information through genetic sequence that controls the division of cells and expression of nucleoprotein, which is unique for each cell. With Wilkins, Watson and Crick received the Nobel Prize for this epoch-making discovery in the year 1962. The next step was to find out why certain cells escape from normal growth control and permit uncontrolled replication. It was thought, the uncontrolled replication is due to mutations in the DNA by carcinogen.
The next discovery of great merit was by two American physiologists Michael J. Bishop and Harold E. Varmus who discovered that the sequences of the genetic codes of RNA virus and animal cells are identical. Bishop and Varmus coined the terms protooncogene and virus oncogene. These two scientists received the Nobel Prize for medicine in 1989.
The readers interested in the study of cancer cannot forget the other Nobel Prize winners in medicine and physiology for their lifelong contribution to the search for the cause of cancer. They are Fritz A. Lipton and Hans A. Koreas (1953) for the study of living cells, J. Lederberg, George W. Beadle and E. L. Tatum (1958), for their work in the genetic transmission of hereditary characteristics, Robert W. Holley, Har Gobind Khorana and Marshal W. Nirenberg (1968) for their contribution to further studies in genetic code. In 1975 David Baltimore and Renato Dulbeccobo received the Nobel Prize for medicine and physiology in recognition of their masterly work on interaction between the cells and their replication.
7In the field of cancer chemotherapy, many scientists in different centers in Europe, the UK and the US have contributed significantly to evolve a therapeutic protocol by animal experiments and phase trials. For the introduction of monoclonal antibodies as a chemotherapeutic agent for the first time in 1975, Kohler and Milstein won the Nobel Prize for medicine in 1984.
Five years prior to the AIDS era, research workers of different centers in big cities in the US, were trying to find the relation between AIDS and microbes, especially the ones targeting T4 helper cells. In 1981, Dr Robert Gallo, the central figure in the discovery of AIDS discovered 3 retroviruses as the causative factors in AIDS. (The term ‘retrovirus’ arises from the fact that in this type of virus the DNA is produced ‘backwards’ from RNA while normally the RNA is produced in a direction ‘forwards’ from the DNA). In the year 1978, Dr Gallo also isolated for the first time, a type of retrovirus HTLV1 causing a rare type of cancer in man known as T cell leukemia. Interestingly, this virus too has tropism for T4 helper cells as in the AIDS virus. The virus can destroy the T helper cells once it gains entry, and by destroying the immunocompetence of the body, can cause T cell leukemia.
The worldwide appearance of acquired immunodeficiency syndrome (AIDS) has given a new dimension to the problems of rare malignancies like Kaposi’s sarcoma and B-cell non-Hodgkin’s lymphoma occurring in the man, woman and child infected with AIDS virus. The type of retrovirus HIV-1 identified in 1978 has profound influence on body’s protective immune system. It also damages the protective immunological surveillance that inhibits the tumor suppressor genes and activates, in turn, the tumor producing genes.
The discovery of the tumor suppressor gene p53 has gone a long way in the advancement of knowledge on control of cell cycle. It is called ‘the guardian of the genome’. With the other genes such as cyclins and growth hormone receptor, p53 is involved in the control of cell cycle with the gene products. It came to prominence in the early 1980 as a tumor antigen (tumor protein 53) and in the late 1980, it was realized that this gene in its mutated form has the ability to produce tumors. Further work on the property of gene unfolded its critical step in the majority of human and rodent tumors. It lies on chromosome 17p and encodes 2.8 kb mRNA. It works in close relation with another gene p21 through its encoded proteins. The loss of normal p53 protein facilitates the emergence of malignant traits in the normal cell.
THE CANCER PATTERN IN INDIA
The problem of cancer is universal. Cancer in all forms causes 12 percent of deaths throughout the world that includes the developed and developing countries. In developed countries, cancer is ranked as the second commonest cause of death (2.5 million), while in developing countries; it is ranked third (3.8 million), next to infectious diseases and cardiovascular diseases.
India is one of the developing countries with a population of 1000 million, and most of the people are engaged in agricultural work and living in villages (700 million). The rest are in the cities and towns engaged in different types of jobs including industrial work. There are nearly 2.5 million persons suffering from cancer at any given time. Around 7,00,00 new cases are added each year. The age-adjusted incidence rate of all cancers varies from 44 to 122 men per 100,000 males and 52 to 128 per 100,000 females in the different8 urban and rural registries. The age adjusted mortality rate is 61 per 100,000 males and 58 per 100,000 females (Mumbai Cancer Registry 2001). The lifetime cumulative risk indicates that on an average one in 10 to 13 people develops cancer in urban areas. The author (J.S.) admits that the populations covered by these registries in the urban and rural areas are small–nearly 5 percent of the total population. It gives some idea of the extent of the problem of cancer in India.
The incidence of cancer in men in the order of the frequency of occurrence is oropharynx, esophagus, stomach, trachea, bronchus and lungs. Tobacco is widely used in India both for chewing and smoking and is thought to be the single major cause of initiating cancer of the oral cavity, pharynx, lungs and the stomach. Added to this poor oral hygiene, inadequate intake of wholesome food and unhygienic environment also contribute to the development of cancer. In the case of women, the occurrence of cancer in the descending order is of the cervix, breast, oral cavity, pharynx and esophagus. Among Indian women the cancer of the breast and cervix forms a large group of 60 percent of all cases. The etiological factors are poor genital hygiene, early marriage, multiple pregnancy and sexual contact with more than one partner.
In India, more people are stricken with cancer in this decade when compared to the earlier decades of the last century. The reasons are many: There is longer life expectancy (It was 27 years in 1930 and now it is around 65), different types of vegetables treated with pesticides, increased use of tobacco, and inhaling noxious fumes expelled from automobiles, heavy industries and chemical factories.
The pattern of cancers is different in different countries. There is a high incidence of gastric cancer in Japan and a lower one in the US and it would be somewhere in the middle in India. The incidence of cervical cancer is high in India and in Colombia (South America) and low in Japan. In south Asian countries, the oral and uterine cancers top the list of malignant tumors especially the uterine cervical cancers. In spite of the fact, that these anatomical regions are accessible for easy and quick physical examination and exfoliative study, the patients come unusually late for treatment in general hospitals. The use of tobacco is more prevalent in 9 men and the cancers related to this habit are seen more in men than in women.
India too is emerging as a great industrial force using nuclear fission for energy. The Atomic Energy Commission has taken steps to guard against any mishaps like the one at Chernobyl and other atomic plants in different parts of the world. The problem of the disposal of atomic waste worries our public health officials.
We have achieved a lot in controlling cancer and treating it. More has to be done. The cancer research has to be taken up with more dedication and vigor. The carcinogens specific in India have to be identified. It is true that there is a lot of suffering among the people in the fringes of our society. Early screening for cervical, breast and colon cancers has to be undertaken on a national level. The major issues like the cost and the patient compliance have to be worked out by public health officials.