Neoplasia

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general characteristics and carcinogenesis

11.1 Dysplasia and neoplasia94
11.2 Carcinogenesis96

Self-assessment: questions100
Self-assessment: answers101

Chapter overview
Neoplasia is abnormal cell growth that does not respond normally to factors controlling growth and differentiation. It is due to genetic abnormalities in the neoplastic cells. The cells form masses (neoplasms or tumours) that may remain confined to the tissue of origin (benign neoplasms) or have the potential to spread to other tissues and organs (malignant neoplasms). Intraepithelial neoplasia is often referred to as dysplasia. Neoplastic transformation (carcinogenesis or oncogenesis) is a multistep process by which cells acquire neoplastic properties and produce tumours.

11.1. Dysplasia and neoplasia

Learning objectives
You should:

• define neoplasm
• distinguish benign from malignant neoplasia
• describe biological characteristics of neoplastic cells that are associated with excessive growth, invasion and metastasis
• discuss dysplasia (intraepithelial neoplasia) and give clinically relevant examples.

Neoplasia

Neoplasia literally means ‘new growth’. A definition of neoplasm is given in Box 15. The term ‘tumour’ (which actually means a swelling) is usually used synonymously with ‘neoplasm’.
Box 15

A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue. The proliferation is purposeless and continues without regard to its effects on the surrounding tissues or the requirements of the organism. The cells do not respond normally to biological constraints on cell growth. These characteristics are due to genetic changes in the cells.
Our current concept of oncogenesis (the process whereby cells become neoplastic) is that neoplasms are derived from stem cells whose normal control of growth and differentiation has been pathologically changed through genetic defects. Stem cells, which have the capacity to divide continuously as well as produce mature differentiated cells, are found throughout the body in labile and stable cell populations. Differentiated cells have specialised functions which are not present in the precursor stem cell. For example, mucin-secreting goblet cells are derived from epithelial stem cells, and mature lymphocytes are derived from lymphoid stem cells.
Although each somatic cell contains the whole human genome, groups of genes can be switched on or off, and this mechanism determines the differentiation of the cell by controlling which genes will be transcribed. This process is controlled by the genetic programming of the cell and the local environment in which it grows (systemic hormones, local growth factors and matrix proteins).
The normal cell signalling and cell division pathways that maintain normal differentiation and growth are subverted by the genetic abnormalities characteristic of neoplasia. Thus, neoplastic cells continue to multiply inappropriately and may show reduced or abnormal functional specialisation. The genetic events involved are considered in more detail in Section 11.2.
Neoplasms (tumours) consist of neoplastic cells together with the connective tissue framework called the stroma. The blood vessels in the stroma represent the blood supply to the neoplastic cells, and the growth of the neoplasm depends on the ability of the neoplastic cells to induce the growth of these new blood vessels. In malignant neoplasms, the stroma often has a characteristic appearance called ‘desmoplasia’ due to the presence of large numbers of active fibroblasts.
Neoplastic cells show morphological changes that allow them to be recognised by pathologists. Sometimes, pathologists refer to these changes as ‘atypia’ in pathology reports. The features may include one or more of:

• variation in cell shape and size (pleomorphism)
• large nuclei in relation to cytoplasm
• dark-staining nuclei (hyperchromatism)
• irregularities of nuclear contour and chromatin pattern
• loss of normal maturation
• increased mitotic figures – some may be atypical, i.e. of abnormal shape
• enlarged nucleoli.
Neoplastic cells may closely resemble their normal counterparts, in which case they are said to be well differentiated. In contrast, tumour cells that bear little resemblance to normal are poorly differentiated. Occasionally, the cells lose all their differentiating features and are called anaplastic or undifferentiated.
It is possible to grow neoplastic cells in culture in the laboratory. As a result of such work, several important differences in the behaviour of neoplastic cells compared with normal cells have been identified. In particular, neoplastic cells show:

• The transformed phenotype (Figure 26), which means that they:

do not require extrinsic growth factors
proliferate to form a colony derived from a single parent stem cell (clone)
show reduced cell cohesiveness
show altered surface antigens
grow to higher cell densities in a haphazard way
do not show normal cell orientation.
• Tumorigenicity, which means that they will grow into tumours when injected into immunosuppressed animals.
• Immortality, which means that they can undergo indefinite replication without showing senescence. In most cases, this is due to the expression of telomerase, an enzyme normally only found in stem cells that prevents the shortening of the telomeres on the ends of chromosomes. (In untransformed cells, the shortening of the telomeres with each cell division limits the number of times a cell can divide.)
• The ability to evade the host defences against malignant cells. Immune cells, principally natural killer cells and T lymphocytes, are able to recognise neoplastic cells because of altered expression of cell surface antigens. If a neoplasm is to grow successfully, it must be able to avoid immune destruction.

The concepts of benign and malignant

Neoplasms are divided into two main types: benign and malignant. Benign tumours remain confined to their tissue of origin, but malignant neoplasms can spread to other tissues and organs. The term ‘cancer’ means ‘malignant neoplasm’.
By definition, benign tumours do not spread beyond their site of origin. However, they may grow to be extremely large and may distort or disrupt local tissues. Thus, a benign tumour can, by virtue of its position and local effects, kill the patient. For example, a benign tumour in a vital area of the brain can be lethal. Benign neoplasms tend to be:

• well circumscribed or encapsulated
• slow growing (low mitotic rate)
• well differentiated, i.e. resemble the tissue of origin.
The defining characteristic of malignant neoplasms is their ability to invade from the site of origin into other tissues. They often (though not always) show the following features:

• poorly circumscribed
• rapid growth
• may be poorly differentiated
• can metastasise
• extensive disease may be associated with cachexia (generalised body wasting).

Spread of malignant neoplasms

Malignant tumours can show local and metastatic spread.

Local invasion

Local invasion is direct spread into tissues adjacent to the cancer. For example, cervical cancer can invade the uterine body, vagina, rectum, urinary bladder and ureters. A special form of local invasion is perineural spread, in which tumour cells acquire the ability to invade along nerves. Tumours showing this feature often spread rapidly into adjacent tissues, and so pathologists search for perineural invasion when examining malignancies under the microscope.

Metastasis

Metastasis is the spread of the tumour to distant sites away from the original tumour. The metastatic deposits are called secondary tumours, while the original tumour is the primary tumour. Metastases may arise from spread via the lymphatics, via the bloodstream, or across body cavities:

• Haematogenous spread: the most common sites for blood-borne metastases are bone, lung, brain and liver, e.g. liver involvement in gastric cancer and bone metastases from breast cancer.
• Direct seeding across cavities (transcoelomic spread), e.g. colorectal cancer can spread across the peritoneal cavity to produce metastases on the peritoneal surfaces of other organs.

Mechanisms of invasion and metastasis

Malignant neoplasms (cancers) can invade other tissues and spread to distant parts of the body. For invasion to occur, the tumour cells must possess these abilities:

• separation from adjacent cells
• attachment to matrix components
• degradation of extracellular matrix
• migration through extracellular matrix.
An important factor in the poor cohesiveness of cancer cells, allowing them to separate from each other, is abnormal expression of cell adhesion molecules. A cell adhesion molecule often down-regulated in epithelial cancers is E-cadherin. Once separated from their fellows, the cells need to attach to matrix components so they can start to move through the matrix; this is accomplished through expression of various receptors such as integrins. Degradation of matrix is performed by proteases which digest components of the extracellular matrix such as collagen; many of these enzymes are members of the matrix metalloproteinase family. These matrix-degrading enzymes produce corridors for invasion through the tissue. Normal tissues produce protease inhibitors but these may be neutralised by tumour cells.
The process of metastasis through blood or lymph to produce secondary tumours requires the tumour cells to exhibit a number of features:

• invasion through extracellular matrix
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