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Phases of Cancer Development

Clinically there are four main types of cancer. Tumors are classified by fetal germ layer. Those arising within the tissues derived from the fetal ectoderm or endoderm are technically carcinomas, include most of the common adult cancers that arise in the skin, and mucous membranes of the respiratory, gastrointestinal and reproductive tracts. Tumors arising from tissues originating from the fetal mesoderm are technically sarcomas and include tumors arising in bone, muscle, connective tissues, blood vessels, etc. In adults these are less common, but in children they are seen more frequently.

Cancer occurs in children with a very different pattern than in adults, with leukemias, brain tumors, sarcomas more common and other ones characteristic of the age group like Wilms tumor of the kidney. Tumors in children are more sensitive to treatments like chemotherapy which children handle better than adults, and in general the results of pediatric cancer treatment are better. In adults, 90% of tumors are carcinomas, while 2% are sarcomas, 4% leukemias and 5% lymphomas. Leukemias are called liquid tumors since they exist mostly in suspension in the blood, while the others are solid tumors.

Cancer has a clonal origin. Malignant transformation of a single cell leads to the progenitor of a tumor that reproduces itself to form the tumor. Tumor cells are unstable genetically. As the cells divide further mutations accumulate resulting in great heterogeneity of both morphology and cellular function as the tumor grows. This heterogeneity is a significant factor in determining both the biology of the tumor (e.g. its ability to metastasize), and its resistance to body defenses and to therapies.

Tumors grow with characteristic growth kinetics, called Gompertzian kinetics. These are exponential-like early on and then show some retardation of the growth as the tumor enlarges. From its origins in a single cell, this means that there is a long latency period between the beginning of the tumor and its clinical detection – as much as 5, 10 or even 15 years with some tumors. The tumor becomes a 1-mm mass (containing about 1 million cells) after about 20 doublings and can be first visualized on X-ray at 27 doublings as a 0.5-cm mass. It becomes palpable (first detection clinically) as a 1.0 cm mass (about a billion cells weighing about a gram) at 30-32 doublings. Thus a tumor is diagnosed late in its natural history after two-thirds or more of its development is over; clinically we deal with the end stages of the disease, even when it is diagnosed "early" by screening. From the point of detection to death is about 3 to 4 years on the average for most solid tumors, but there is a very wide variation depending on tumor type. At death one might expect a tumor load of a kilogram or more. Thus cancer is a chronic disease which lasts most of a patient’s lifetime, and becomes symptomatic and a clinical problem only at the end stages of its development. These kinetics are also essential for designing the strategies used for both chemotherapy and radiotherapy.

The cancer societies educate the public about cancer’s 7 warning signals.

• Change in bowel or bladder habits
• A sore that does not heal
• Unusual bleeding or discharge
• Thickening or lump in the breast or elsewhere
• Indigestion or difficulty in swallowing
• Obvious change in a wart or mole
• Nagging cough or hoarseness

However, these symptoms are often too late in the natural history of the disease for sure and can be confused with unrelated other disease processes. Tumors become symptomatic in four ways:

• As a mass – a hard, painless lump, with or without fixation to surrounding normal tissues, which can ulcerate and become secondarily infected, which can press and erode vital structures impairing function (e.g. in the central nervous system) or bleeding and perforation or obstruction of hollow organs.
• Through ectopic secretion of normal or abnormal hormones which arise from derepression of fetal genes. There is a great similarity in the dedifferentiation seen in malignant cells with that of fetal tissues. The process of migration of the individual fetal cells which are the precursor to the diaphragm, for example, from the neck along with its cervical nerve supply to the thoraco-abdominal junction resembles metastasis, except that it is rigorously controlled.
• Through systemic effects such as weight loss, fatigue, or anorexia, some of which is mediated by cytokines such as tumor necrosis factor.
• And through the production of pain, which up to 80% of cancer patients will experience at some time in the course of the disease.

In the clinic, staging is carefully done using international classification systems to allow comparisons of statistics and clinical trials. The commonest used method is the TNM classification (Tumor, Node, Metastasis) which is correlated with staging. Staging correlates with survival: overall about 40% surviving at 10 years after diagnosis for local disease; about 25% at 10 years for regional disease; and most patients with distant disease succumbing by 5 years. Staging measures the burden and distribution of disease in the individual patient and shows where the tumor is in its natural history. From this information estimates of prognosis can be made. The details of treatment plans also depend on staging, especially the relative importance of locoregional approaches (surgery and radiotherapy) compared to systemic treatments such as chemotherapy, hormones and biological therapies.

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