Neoplasia neoplasm is an abnormal mass of tissue as a result of neoplasia



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NEOPLASIA

Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia (new growth in Greek) is the abnormal proliferation of cells, it is a widespread and potentially grave growth abnormality (dystrophic proliferation). The growth of this clone of cells exceeds, and is uncoordinated with, that of the normal tissues around it. It usually causes a lump or tumor.

Cancer is a disease of growth, division and cell differentiation, it is the result of mutation of genes controlling these processes (protooncogenes and cancer suppressor genes).

Cancer is synonymous with malignant tumor; the Latin cancer is actually a literal translation of the Greek karkinos for crab, a common creature on Mediterranean shores. In the Hippocratic books, karkinos and karkinoma are used for conditions that we would almost certainly call carcinoma (epithelial cancer) or, more generally, cancer. There seem to have been many reasons for borrowing the image of the crab, and the choice was extraordinarily successful: the name of the innocent crustacean has become a sinister metaphor, even for the destructive ills of society



Tumor is a typical pathologic process characterized by irregulated limitless growth of the tissue, which is not connected with the general structure of the impaired organ and its functions.

Tumor is growing from itself, i.e. it grows as a result of reproduction of even one malignant cell. The tissue of tumors differs from the original one by structure, physical and chemical, biochemical, functional and other signs. It is called atypism. These changes indicate anaplasia that is returning of the cell to its embryonic state and also metaplasia — acquisition of properties of other tissue.



Table 21. Epidemiology of human cancer

Male

Female

most common (by occurrence)

most common (by mortality)

most common (by occurrence)

most common (by mortality)

prostate cancer (25%)

lung cancer (31%)

breast cancer (26%)

lung cancer (26%)

lung cancer (15%)

prostate cancer (10%)

lung cancer (14%)

breast cancer (15%)

colorectal cancer (10%)

colorectal cancer (8%)

colorectal cancer (10%)

colorectal cancer (9%)

bladder cancer (7%)

pancreatic cancer (6%)

endometrial cancer (7%)

pancreatic cancer (6%)

non-Hodgkin lymphoma (5%)

liver & intrahepatic bile duct (4%)

non-Hodgkin lymphoma (4%)

ovarian cancer (6%)

Cancer is a global problem, and with reference to the globe, it is also a spotty problem. By definition, the task of epidemiology is to explain why a particular patient developed a particular disease at a particular time and place. Its ultimate goal is to find all causes of all diseases and to suggest preventive measures for every one.

The two basic rules of cancer epidemiology are that all types of cancer can occur everywhere, and that the incidence of each type varies from place to place. The lowest incidence of a particular cancer observed anywhere on the globe is taken to represent the baseline for that cancer, which is due to shared genetic and/or environmental factors. Any higher incidence is interpreted as reflecting some special local cause, usually environmental. This rule has been exploited for detecting causes in high-incidence populations.

We should recall here that incidence is the number of new cases in a population during a given period. Prevalence is the number of existing cases at a given time.



  1. Types of tumors

When discussing human tumors, we will use the traditional distinction between benign tumors (slowly growing, noninfiltrating, not fatal) and malignant tumors (more rapidly growing, infiltrating, metastasizing, and if untreated fatal). When discussing experimental carcinogenesis, we will follow the party line of the experts: tumors are malignant or on the way to malignancy.

A benign tumor is a tumor that lacks all three of the malignant properties of a cancer. Thus, by definition, a benign tumor does not grow in an unlimited, aggressive manner, does not invade surrounding tissues, and does not metastasize. Common examples of benign tumors include moles and uterine fibroids.

The term "benign" implies a mild and nonprogressive disease, and indeed, many kinds of benign tumor are harmless to the health. However, some neoplasms which are defined as 'benign tumors' because they lack the invasive properties of a cancer, may still produce negative health effects. Examples of this include tumors which produce a "mass effect" (compression of vital organs such as blood vessels), or "functional" tumors of endocrine tissues, which may overproduce certain hormones (examples include thyroid adenomas, adrenocortical adenomas, and pituitary adenomas).

Benign tumors typically are encapsulated, which inhibits their ability to behave in a malignant manner. Nonetheless, many types of benign tumors have the potential to become malignant and some types, such as teratoma, are notorious for this.



Malignant neoplasm or malignant tumor: synonymous with cancer.

Table 22. Summary of features differentiating benign and malignant
neoplasms.

Feature

In Benign Tumors

In Malignant Tumors

Rate of growth

Slow

Fast

Mode of growth

Expansile

Infiltrative

General effects

Uncommon (except endocrine)

Common

Metastases

No

Common

Recurrence after removal

Rare

Common

Gross:







Capsule

Common

Pseudocapsule

Necrosis

Rare

Common

Ulceration

Rare

Common

Microscopic:







Atypia

Mild

Severe

Pleomorphism

Mild

Severe

Mitoses

Few

Many

Nuclear/cytoplasmic ratio

Normal

Increased

Nucleolus

Normal

Prominent

Ploidy

Often normal

Usually abnormal

  1. Grading and staging of cancer

Methods to quantify the probable clinical aggressiveness of a given neoplasm and to express its apparent extent and spread in the individual patient are necessary for comparisons of end results of various forms of treatment.

The grading of a cancer attempts to establish some estimate of its aggressiveness or level of malignancy based on the cytologic differentiation of tumor cells and the number of mitoses within the tumor. The cancer may be classified as grade I, II, III, or IV, in order of increasing anaplasia.

Staging of cancers is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of metastases. Two methods of staging are currently in use: the TNM system (T, primary tumor; N, regional lymph node involvement; M, metastases). In the TNM system, T1, T2, T3, and T4 describe the increasing size of the primary lesion; N0, N1, N2, and N3 indicate progressively advancing node involvement; and M0 and M1 reflect the absence or presence of distant metastases.


  1. Etiology and pathogenesis

Risk factors

Some mistakes in DNA replication throughout a lifetime are inevitable. However, certain conditions or behaviors, known as risk factors, can increase or decrease the likelihood of a mutation arising and a mutated cell being promoted until it is cancerous.



Geographic variations in the overall incidence of cancer and in the incidence of specific types of cancer also occur from one country to another, from one city to another, and from urban to rural areas. Detailed epidemiologic case control studies have sometimes uncovered associations with high-risk occupations, diet, environmental carcinogens, or endemic viruses; other occurrences remain unexplained. For example, the high incidence of stomach cancer in Japan has been related to diet (smoked raw fish). This type of cancer does not appear to be genetically determined, because Japanese emigrating to the United States show within a single generation the lower incidence of stomach cancer demonstrated by native-born Americans.

Behavioral risk factors. Certain behaviors increase the likelihood that an individual will be frequently exposed to cancer-causing stimuli. Behavioral risk factors include cigarette smoking and diets rich in animal fat and preserved meats. Approximately a third of all cancers can be attributed to cigarette smoking, and a third to diet. Obesity also may be an independent risk factor for cancer because of the increased accumulation of fat-soluble toxins and potentially carcinogenic hormones in fatty tissue. Even a low level of alcohol consumption is linked to an increase in breast cancer, as is a sedentary lifestyle. Other behavioral risk factors include those associated with sexual behavior. A high number of sexual partners and an early onset of sexual activity increase the risk of becoming infected with the human papilloma virus (HPV), which is associated with genital neoplasms, and the AIDS virus, which is associated with Kaposi's sarcoma.



Hormonal Risk Factors. Estrogen may act as a promoter for certain cancers, such as breast and endometrial cancer. Because estrogen levels are high in menstruating women, the risk for developing breast cancer is increased in women who started menstruating early and reached menopause late. Delayed childbearing or choosing not to bear children increases the risk of breast cancer. Estrogen replacement therapy in postmenopausal women appears to be associated with an increase in the risk of breast cancer.

Inherited Risk Factors. A family history of cancer, especially clustered as one type, is a risk factor for developing cancer. Genetic tendencies for carcinogenesis may involve fragile or mutated tumor suppressor genes, susceptibility to certain mutagens or promoters, faulty proofreading enzymes, or a poorly functioning immune system. Inherited defects in the p53 gene have been documented to be associated with a high risk of cancer. Certain cancers have a higher tendency to run in families than others. For example, although most cases of colon cancer arise spontaneously, some families carry mutations that increase the risk of this disease.

Pediatric cancers likely have a genetic component. In children, the development of cancer is accelerated from several decades to only one or two decades. Acceleration may occur if a child inherits in the germ line (egg or sperm) one defective gene controlling a tumor suppressor or proto-oncogene product or develops such a mutation early in embryogenesis. Later, a second gene error would cause early cancer growth. Similarly, inheriting defective genes for proofreading enzymes would increase the risk of early cancer development.

History of Associated Diseases. Perhaps the most important finding in the history of a patient with suspected cancer is a record of diagnosis or treatment of previous cancer which greatly increases the chances that the current illness represents either a metastasis or a second primary tumor. Statistics show that patients who have had cancer—have a much higher incidence of a second cancer, particularly in the same tissue. For example, cancer in one breast increases the chances of cancer in the opposite breast. Second cancers of a different type—particularly leukemia and sarcomas—also occur as a complication of chemotherapy and radiation used to treat the first cancer.

In addition, certain disorders that in themselves are nonneoplastic carry an associated higher risk of development of cancer and are considered preneoplastic diseases. These diseases are uncommon, but together they constitute a significant group of risk factors



Table 23. The preneoplastic diseases

Nonneoplastic or preneoplastic condition

Neoplasm

Down Syndrome (trisomy 21)

Acute myeloid leukemia

Xeroderma pigmentosum (plus sun exposure)-

Squamous cancer of skin

Gastric atrophy (pernicious anemia) -

Gastric cancer

Factors that are protective against cancer development

Studies suggest that women who breastfeed for at least 6 consecutive months have a reduced risk of developing breast cancer. In addition, women who have had multiple pregnancies have a reduced risk of breast cancer. Progesterone is high during pregnancy and appears to be protective against breast cancer by inhibiting the stimulatory effects of estrogen.

Dietary factors are important in reducing cancer risk. Diets rich in substances known to scavenge or remove dangerous free radicals, called free-radical scavengers or antioxidants, may reduce the risk of certain cancers. These substances include vitamins A, E, and C and folic acid, all of which are prevalent in green, leafy and colorful vegetables and fruits.

Mechanisms of gene activation & inactivation

Cancer is a diverse class of diseases which differ widely in their causes and biology. Any organism, even plants, can acquire cancer. Nearly all known cancers arise gradually, as errors build up in the cancer cell and its progeny.

Anything which replicates (our cells) will probabilistically suffer from errors (mutations). Unless error correction and prevention is properly carried out, the errors will survive, and might be passed along to daughter cells. Normally, the body safeguards against cancer via numerous methods, such as: apoptosis, helper molecules (some DNA polymerases), possibly senescence, etc. However these error-correction methods often fail in small ways, especially in environments that make errors more likely to arise and propagate. For example, such environments can include the presence of disruptive substances called carcinogens, or periodic injury (physical, heat, etc.), or environments that cells did not evolve to withstand, such as hypoxia (see subsections). Cancer is thus a progressive disease, and these progressive errors slowly accumulate until a cell begins to act contrary to its function in the animal.

It has been suggested that neoplastic transformation occurs as a result of activation (or derepression) of growth promoter genes (proto-oncogenes) or inactivation or loss of suppressor genes. Activation is a functional concept whereby the normal action of growth regulation is diverted into oncogenesis. The resultant activated proto-oncogene is referred to as an activated oncogene (or a mutant oncogene, if structurally changed), or simply as a cellular oncogene (c-onc). Activation and inactivation may occur through several mechanisms: (1) mutation, including single nucleotide loss (frameshift) or substitution (nonsense or missense codon), codon loss, gene deletion or more major chromosomal loss; (2) translocation to a different part of the genome where regulatory influences may favor inappropriate expression or repression; (3) insertion of an oncogenic virus at an adjacent site; (4) amplification (production of multiple copies of the proto-oncogenes), which appear as additional chromosome bands or extra DNA fragments (double minutes); (5) introduction of viral oncogenes; or (6) derepression (loss of suppressor control).



Carcinogens

An agent that causes neoplasms is an oncogenic agent; an agent causing a malignant neoplasm (cancer) is a carcinogenic agent. Carcinogens are substances that are known to cause cancer or at least produce an increased incidence of cancer in an animal or human population. Many carcinogens have been identified in experimental animals, but because of dose-related effects and the metabolic differences among species, the relevance of these studies to humans is not always clear. It is important to stress that (1) the cause of most common human cancers is unknown; (2) most cases of cancer are probably multifactorial in origin; and (3) except for cigarette smoking, the agents discussed below have been implicated in only a small percentage of cases.



  1. Chemical carcinogenesis

It has been over 200 years since the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot. A few years later, based on this observation, the Danish Chimney Sweeps Guild ruled that its members must bathe daily. No public health measure since that time has achieved so much in the control of a form of cancer. Since that time, hundreds of chemicals have been shown to be carcinogenic in animals.

Main characteristic of chemicals carcinogens.

  • They are of extremely diverse structure and include natural and synthetic products.

  • Some are direct reacting and require no chemical transformation to induce carcinogenicity, but most are indirect reacting and become active only after metabolic conversion. Such agents are referred to as procarcinogens, and their active end products are called ultimate carcinogens.

  • All direct-reacting and ultimate chemical carcinogens are highly reactive electrophiles (i.e., have electron-deficient atoms) that react with the electron-rich atoms in RNA, cellular proteins, and, mainly, DNA.

  • The carcinogenicity of some chemicals is augmented by agents that by themselves have little, if any, transforming activity. Such augmenting agents traditionally have been called promoters; however, many carcinogens have no requirement for promoting agents.

  • Several chemical carcinogens may act in concert with other types of carcinogenic influences (e.g., viruses or radiation) to induce neoplasia.

Direct-acting agents, as already noted, require no metabolic conversion to become carcinogenic. They are in general weak carcinogens but are important because some of them are cancer chemotherapeutic drugs (e.g., alkylating agents) that have successfully cured, controlled, or delayed recurrence of certain types of cancer (e.g., leukemia, lymphoma). This situation is even more tragic when their initial use has been for non-neoplastic disorders, such as rheumatoid arthritis. The risk of induced cancer is low, but the fact that it exists dictates judicious use of such agents.

The designation indirect-acting agent refers to chemicals that require metabolic conversion before they become active. Some of the most potent indirect chemical carcinogens-the polycyclic hydrocarbons-are present in fossil fuels. Polycyclic agents may be produced in the combustion of organic substances. For example, benzo[a]pyrene and other carcinogens are formed in the high-temperature combustion of tobacco in cigarette smoking. These products are implicated in the causation of lung cancer in cigarette smokers.

Polycyclic hydrocarbons also may be produced from animal fats during the process of broiling meats and are present in smoked meats and fish. The principal active products in many hydrocarbons are epoxides, which form covalent adducts (addition products) with molecules in the cell, principally DNA, but also with RNA and proteins.

Aflatoxin B1 is of interest because it is a naturally occurring agent produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts. There is a strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East.

Saccharin and cyclamates have been incriminated as carcinogens in experimental animals, but because induction of cancer with these artificial sweeteners requires extremely large doses, their role in human carcinogenesis remains in doubt. Finally, vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls (PCBs) are potential carcinogens in the workplace and about the house.

Mechanisms of action of chemical carcinogens

Because malignant transformation results from mutations that affect protooncogenes and cancer suppressor genes, it should come as no surprise that most chemical carcinogens are mutagenic. Although any gene may be the target of chemical carcinogens, RAS gene mutations are particularly common in several chemically induced cancers in rodents. Among tumor suppressor genes, TP53 is an important target. Specific chemical carcinogens, such as aflatoxin B1, produce characteristic mutations in the TP53 gene. The association is sufficiently strong to incriminate aflatoxin, if the analysis of the TP53 gene reveals the signature mutation. These associations are proving useful tools in epidemiologic studies of chemical carcinogenesis.

It was mentioned earlier that carcinogenicity of some chemicals is augmented by subsequent administration of promoters (e.g., phorbol esters, hormones, phenols, and drugs) that by themselves are nontumorigenic. To be effective, repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator. The initiation-promotion sequence of chemical carcinogenesis raises an important question: Since promoters are not mutagenic, how do they contribute to tumorigenesis? Although the effects of tumor promoters are pleiotropic, induction of cell proliferation is a sine qua non of tumor promotion. Tetra-decanoylphorbol-acetate (TPA), a phorbol ester and the best-studied tumor promoter, is a powerful activator of protein kinase C, an enzyme that is a crucial component of several signal transduction pathways, including those activated by growth factors. TPA also causes growth factor secretion by some cells. It seems most likely that while the application of an initiator may cause the mutational activation of an oncogene such as RAS, subsequent application of promoters leads to clonal expansion of initiated (mutated) cells. Such cells (especially after RAS activation) have reduced growth factor requirements and may be less responsive to growth-inhibitory signals in their extracellular milieu. Forced to proliferate, the initiated clone of cells suffers additional mutations, developing eventually into a malignant tumor.

The concept that sustained cell proliferation increases the risk of mutagenesis, and hence neoplastic transformation, is also applicable to human carcinogenesis. The influence of estrogens on the occurrence of breast cancers may relate in part to the proliferative effects of estrogen on mammary ductal epithelium. The fact that many breast cancers express estrogen receptors and benefit from estrogen receptor antagonists supports a role for estrogen in breast cancer.

It must be emphasized that carcinogen-induced damage to DNA does not necessarily lead to initiation of cancer. Several forms of DNA damage (incurred spontaneously or through the action of carcinogens) can be repaired by cellular enzymes. Were this not the case, the incidence of environmentally induced cancer in all likelihood would be much higher.



  1. Physical carcinogenesis

In group of physical factors of tumorogenesis the most important and most often is radiation, whatever its source-UV rays of sunlight, x-rays, nuclear fission, radionuclides is an established carcinogen. The evidence is so voluminous that only a few examples are given. Many of the pioneers in the development of roentgen rays developed skin cancers. Miners of radioactive elements have suffered a ten-fold increased incidence of lung cancers. Follow-up of survivors of the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia-principally acute and chronic myelocytic leukemia-after an average latent period of about 7 years. Decades later, the leukemia risk for individuals heavily exposed is still above the level for control populations, as is the mortality rate from thyroid, breast, colon, and pulmonary carcinomas and others. The nuclear power accident at Chernobyl in the former Soviet Union continues to exact its toll in the form of high cancer incidence in the surrounding areas. Even therapeutic irradiation has been documented to be carcinogenic. Papillary thyroid cancers have developed in approximately 9% of individuals exposed during infancy and childhood to head and neck irradiation.

It is abundantly clear that radiation is strongly oncogenic. This effect of ionizing radiation is related to its mutagenic effects; it causes chromosome breakage, translocations, and, less frequently, point mutations. This effects may be due to activation of lipid peroxidation. Biologically, double-stranded DNA breaks seem to be the most important for radiation carcinogenesis. There also is some evidence that nonlethal doses of radiation may induce genomic instability, favoring carcinogenesis. Because the latent period of irradiation-associated cancers is extremely long, it seems that cancers emerge only after the progeny of initially damaged cells accumulate additional mutations, induced possibly by other environmental factors.

The oncogenic effect of UV rays merits special mention because it highlights the importance of DNA repair in carcinogenesis. Natural UV radiation derived from the sun can cause skin cancers (melanomas, squamous cell carcinomas, and basal cell carcinomas). At greatest risk are fair-skinned people who live in locales that receive a great deal of sunlight. Cancers of the exposed skin are particularly common in Australia and New Zealand. Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation, whereas melanomas are associated with intense intermittent exposure-as occurs with sunbathing. UV light has several biologic effects on cells. Of particular relevance to carcinogenesis is the ability to damage DNA by forming pyrimidine dimers. This type of DNA damage is repaired by a complex set of proteins that effect nucleotide excision repair. With extensive exposure to UV light, the repair systems may be overwhelmed, and skin cancer results. The importance of nucleotide excision repair is illustrated dramatically in an inherited disease called xeroderma pigmentosum. In these individuals, the nucleotide excision repair mechanism is defective or deficient, and there is a greatly increased predisposition to skin cancers. UV light characteristically causes mutations in the TP53 gene. Three other disorders of DNA repair and genomic instability-ataxia-telangiectasia, Fanconi anemia, and Bloom syndrome-also are characterized by an increased risk of cancer, related to some inability to repair environmentally induced DNA damage.

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