INTRODUCTION

Neoplasia literally means "new growth", and this tissue growth is called NEOPLASM. A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues, and persists in the same excessive manner after cessation of the stimulus that evoked the change. The key features of neoplasia that distinguishes it from other forms of cell proliferation therefore are:

1] Excessive tissue growth
2] Lack of responsiveness to control  mechanisms
3] Lack of dependence on the  continued presence of the  stimulus

There are several commonly used synonyms for neoplasms. The term TUMOUR strictly speaking means tissue swelling or mass, but by common usage has come to mean neoplasm. CANCER is a lay  term used to mean malignant neoplasm.
 

CHARACTERISTICS OF NEOPLASTIC CELLS

Neoplastic cells, particularly those of the malignant neoplasms differ in many ways from normal cells. Given that neoplasms represent uncontrolled growth of certain cells, it clearly is important to attempt to understand those control mechanisms that regulate cell growth, usually studied using cell cultures.

When normal cells are grown in vitro, they spread out to form a single sheet (or monolayer) of cells. Growth ceases when the cells reach a certain density and the cells remain quiescent but healthy. This process is known as DENSITY-DEPENDENT INHIBITION or CONTACT INHIBITION of growth. In contrast, neoplastic cells, particularly malignant cells grow in haphazard way, pile up into multiple layers, and are much less responsive to cell density-dependent mechanisms of growth control. These cells tend to grow until they exhaust the medium of nutrients, and these characteristics may be induced by treatment with carcinogens (neoplasm inducing agent; see later), the process being known as neoplastic TRANSFORMATION. Morphologically, transformed cells exhibit the following characteristics:

1] May or may not resemble cells of origin (anaplasia and pleomorphism are common)

2] Increased nucleus to cytoplasmic ratio; nuclei enlarged, hyperchromatic and may be multinucleated

3] High mitotic rate

4] Lacks orientation to adjacent cells

5] Decreased rough endoplasmic reticulum and increased free ribosomes

Besides morphological changes in neoplastic cells, transformed cells exhibit the following characteristics:

1] Transplantability - will grow in tissue culture or in syngeneic host

2] Immortality - will divide and replicate indefinitely provided that nutrients required for growth are present

3] Decreased sensitivity to density dependent inhibition of growth

4] Tumorigenicity - forms tumours in syngeneic host

5] Antigenic changes

6] Changes in karyotype - chromosomal damage or alterations in base pairs may be basic to the induction of neoplasia; observed karyotypic changes are rarely characteristics of any one tumour

7] Changes in Cell Biochemistry - neoplastic cells contain less cyclic adenosine monophosphate (cAMP) and more cyclic guanosine monophosphate (cGMP) than normal cell; absence of normal enzymes or the presence of abnormal ones can occur
 

CLASSIFICATION OF NEOPLASM

Neoplasms are named according to the features of differentiation that can be recognised on histologic examination, and reflects the tissue of origin. Nomenclature and classification are important as they form the basis of the language by which pathologists and clinicians discuss the nature and significance of the lesion to one another.

Neoplasms are classified in several ways. One way of classification is based on the tissue origin  (Histogenetic) as 1] Mesenchymal or 2] Epithelial in origin. Most are of one neoplastic cell type and fit into one or the other of these two groups. A few types of neoplasm contain more than one neoplastic cell type. When they are derived from the one embryonic germ layer, they are called Mixed Neoplasm (e.g. mammary tumours in dogs in which proliferating epithelial tissue is intermixed with mesenchymal components, bone and cartilage).

A TERATOMA is a neoplasm containing tissues derived from more than one germ cell layer, and may contain any number of tissues of any type including bone, skin, nervous tissue, muscle, hair and others.
Another classification is based on the growth behaviour of neoplastic cells (Behavioral). The terms Benign Neoplasm describes those which are relatively inoffensive, and Malignant Neoplasm for those which are aggressive and potentially life threatening (see table comparing the characteristics of benign and malignant neoplasms on proceeding page). Most often, the histogenetic and behavioral classification schemes are used in naming neoplasms. Benign neoplasms are named by adding the suffix "-oma" to a prefix suggesting the tissue origin (e.g. benign neoplasm derived from fibroblast is called fibroma). Benign neoplasms derived from glandular epithelia are called Adenomas. This term refers to both those with a solid lobular pattern of growth and those with recognisable tubules, ducts or acini. Because the term adenoma is nonspecific, the tissue of origin is usually shown (e.g. adenoma of sweat gland, adenoma of thyroid gland, or adenoma of adrenal cortex). Also, many modifying terms are applied to the names of neoplasm of epithelial origin. For example, cystadenoma describes an adenoma in which the glandular spaces are cystic; papillary adenoma is one in which branching finger-like processes of neoplastic tissue extend into the lumen; ductular adenoma is one derived from ducts. Papillary neoplastic masses growing at a surface are known as polyps or papillomas.

Malignant neoplasms of mesenchymal origin are called sarcoma. As in their benign equivalent, a prefix is used to suggest the tissue of origin (e.g. malignant neoplasm of fibroblast is called fibrosarcoma). Malignant neoplasms of epithelial cells are called carcinoma. Then, only those that form recognisable ducts, tubules or acini are called adenocarcinoma. Those that form solid pattern are called simply as carcinoma (e.g. those forming stratified squamous epithelium is called squamous cell carcinoma). Again, if the tissue of origin is recognisable, it is included in the name (e.g. adenocarcinoma of sweat gland; adenocarcinoma of adrenal cortex). Some neoplasms fail to mimic their tissue of origin sufficiently for it to be recognised. In such a case, the neoplasm is said to be poorly differentiated sarcoma or carcinoma as the case may be.

Despite these rules for classifying and naming neoplasms, inconsistencies persist. Neoplasms do not always fall neatly into one or the other category, but a spectrum between completely benign and highly malignant exists and errors are bound to occur in trying to predict the future behaviour of a neoplasm.
 

FEATURES OF NEOPLASTIC CELL  DIFFERENTIATION
 

The differentiation of neoplastic cells refers to the degree to which they resemble morphologically and functionally the tissue from which they originate. Again, there is great variability in the degree of differentiation. Benign tumours usually are well differentiated and resemble the tissue of origin, both cytological and architecturally.

Malignant tumours on the other hand vary greatly in the degree to which they differentiate. But generally they exhibit some degree of ANAPLASIA. Anaplasia is failure of cells to differentiate or loss of differentiation, and is one of the most important morphologic features of malignancy. Anaplasia should not be thought of as dedifferentiation, which would imply that cells already differentiated revert to a more primitive form. It is not generally accepted that this can occur. Anaplastic cells usually exhibit pleomorphism. Their nuclei are often large, hyperchromatic or vesicular, have an abnormal shape and may contain one or more prominent nucleoli. The nuclear to cytoplasmic ratio are usually abnormal. Besides these cytological features, the cells in malignant neoplasms often do not grow in well-differentiated architectural patterns, making it difficult to or impossible to classify such neoplasms.

Well-differentiated neoplasms may retain the functional characteristics of the parent tissue. Thus, glandular adenomas may secrete mucus and endocrine adenomas may secrete hormones. Functional activity is in fact the basis on which the origin of many neoplasms may be recognised (e.g. melanomas produce melanin, osteosarcomas produce osteoid, and adenocarcinoma of thyroid produce colloid).

The idea that neoplastic cells divide at a more rapid rate than normal tissue is not true. Frequently, the cell cycle time for neoplastic cells is longer than that of the normal germinal cells from which they are derived. The actual growth rate of neoplasm like that of the normal tissue is decided by the 1]length of the mitotic cycle, 2] the growth fraction (or proportion of cells in mitosis) and 3] the rate of loss of cells from the neoplasms (i.e. through necrosis and apoptosis). What is important is the relative proportion of neoplastic cells in mitosis, and this decides the rate of growth of neoplastic tissue. In many cells, full differentiation precludes further mitotic division. Thus, the degree of differentiation decides the growth fraction of neoplasms. Therefore, well-differentiated neoplasms (i.e. benign neoplasms) contain high proportion of cells unable to divide and so grow slowly. Conversely, poorly differentiated neoplasms (i.e. malignant neoplasms) often contain many cells in the growth fraction and usually grow rapidly.
 

SPREAD OF TUMOURS: INVASION AND METASTASIS

Benign tumours are generally noninvasive, are localised, clearly demarcated from the surrounding tissue and are often but not invariably separated from it by a capsule or rim of normal connective tissue. The latter may be derived from compressed pre-existing stroma or may be part of the stroma of neoplasm. Benign neoplasm usually grows by expansion.

Malignant neoplasms, in contrast, usually exhibit local invasiveness or infiltration, meaning they extend into and may cause considerable destruction of surrounding tissue. Malignant neoplasms also have the potential to metastasize or spread to distant sites not directly adjacent with the primary mass. Neoplasms that metastasize are unequivocally malignant. Metastasis may occur by via the following routes:

 1] Lymphatics
 2] Blood vessels
 3] Coelomic spaces
 4] Epithelial cavities

The processes by which tumour cells spread from one site to another include the following:

 1] Embolism
 2] Vascular invasion
 3] Exfoliation and implantation
 4] Transplantation

The mechanism that account for the ability of malignant cells to invade tissues is poorly understood. Several theories have been proposed. For example, it has been proposed that mechanical pressure resulting from rapid growth results in neoplastic cells being forced into the surrounding tissue. Another is that neoplastic cells produce enzymes that can degrade adjacent tissues, and this includes lysosomal hydrolases, collagenase and plasminogen activator. Recent information suggests that motility of neoplastic cells may be an important factor in invasiveness. However, no single mechanism could fully explain the invasive feature of malignant neoplasms and conflicting evidences exist.

The understanding of tumour metastasis by mere appreciation of the mechanisms and the routes taken by neoplastic cells is certainly an oversimplification of the process. For tumour tissues to successfully form metastases, it must complete the following steps:

1] Release from site of origin
2] Transportation
3] Lodgment in distant site
4] Growth and survival

Metastasis therefore is a selective process and only those cells able to satisfy all these steps can produce metastasis.
 

EFFECTS OF TUMOURS ON HOST

Neoplasms cause harm to the host in several ways as follows:

1] Functional tumours - some tumours retain their functional ability and secrete substances that may cause disease in the host (e.g. functional tumour of parathyroid produce hyperparathyroidism)

2] Effusion - some tumours produce secretory products or cell debris that may cause altered blood flow or decreased lymphatic drainage, or obstruction of ducts

3] Paraneoplastic syndromes - cells which become neoplastic may make altered products or because of gene deregulation may make products characteristics of other cells and cause clinical abnormalities in the host.

5] Production of onco-fetal antigens - many tumours bear new antigens not found on normal host cells. These antigens are known by several names as tumour specific antigens (TSA), tumour specific transplantation antigen (TSTA), or tumour associated transplantation antigens (TATA). Some of these transplantation antigens sensitizes the host's immune system and cause an immune reaction to the neoplastic tissue mass. Some are immunosuppressive and favor growth of neoplasm.

Obviously, malignant neoplasm because of their invasive nature and ability to metastasize will cause more harm to the host than benign tumours. However, benign tumours can have devastating effects as follows:

1] Pressure effects - any space occupying lesion can lead to dysfunction of an organ (e.g. benign neoplasm of the brain cause local destruction of neuropil and can produce severe illness and eventually death of the animal)

2] Obstruction - benign neoplasm may compress hollow organs (e.g. compression of bile ducts lead to massive destruction of liver tissue).

3] Ulceration, haemorrhage, infarction - some may cause massive blood loss that leads to death following ulceration, perforation or rupture of the organ; or necrotic neoplastic cells, or tumour emboli may lodge at arteries and cause infarction or congestion in an organ

4] Hormone production

5] Malignant transformation - some benign neoplasm may progress to form malignant neoplasm
 

AETIOLOGY OF NEOPLASIA

The exact aetiology of most spontaneous neoplasm is unknown. Epidemiological data has led to association of certain agents with certain cancer types. Animal experimentation has confirmed their carcinogenicity. Other studies have suggested an infectious aetiology that has been confirmed for some spontaneous tumours. Substances that cause neoplasia are called CARCINOGENS or ONCOGENS. More specifically, carcinogens may be defined as any substance or agent which produces, in exposed individuals, an incidence of neoplasia greater than that observed in those which are unexposed. Classes of carcinogens include the following:

1] Direct-reacting carcinogen - reactive moieties that require no activation by biologic processes

2] Procarcinogen - agents that must be metabolised in the animal body to the "proximate or ultimate" carcinogen.

3] Initiator - may be direct-reacting or procarcinogens or may not be carcinogenic per se but are capable of initiating a change in the cell which will lead to transformation

4] Promoter (Co-carcinogen) - agents which when applied after initiation promotes the development of tumours

5] Complete carcinogen - act as both initiator and promoter

Known carcinogens fall into three major categories: 1] Physical agents, 2] Chemicals, and 3] Viruses.

Physical agents

Ionising radiation has some mutational effects on cells that possibly lead to neoplastic transformation (e.g. High incidence of neoplasia in survivors of atomic bomb explosions). Ultraviolet light cause mutational effect and damage DNA in cells (e.g. skin cancer in cats, cattle, and man). Trauma such as burns acts as "co-carcinogen" by increasing the mitotic rate (reparative hyperplasia). Solid state (e.g. bone pins may cause osteosarcoma) produces neoplasia probably due to chronic irritation.

Chemical carcinogens

Many chemical carcinogens are procarcinogens and must undergo cellular metabolism to produce the ultimate or proximate carcinogen. For example, aflatoxin and polycyclic hydrocarbons are metabolised to epoxides that are the true carcinogens. Types of chemical carcinogens include naturally occurring substances (e.g. aflatoxin, nitrosamines, betel nut, cycasin) and man-made chemicals (e.g. polycyclic aromatic hydrocarbons, azo dyes, saccharine, polyvinyl chloride)

Oncogenic viruses

Both DNA and RNA viruses cause tumours. Oncogenic DNA viruses include adenovirus, herpesvirus, papovavirus, and poxvirus. Of these, herpesviruses are the most important oncogenic DNA viruses and cause malignant lymphoid neoplasm (lymphosarcoma) in rabbits, guinea pigs, non-human primates, and chickens (Marek's disease).

All oncogenic RNA viruses belong to the retrovirus, so named because they possess an enzyme called reverse transcriptase or more correctly RNA-dependent DNA polymerase. This enzyme is capable of forming DNA using an RNA template, a feat which mammalian cells cannot normally accomplish. Retroviruses cause lymphosarcomas and sarcomas in many species including chickens, mice, cats, cattle and apes.
 

THEORIES IN CARCINOGENESIS
 

At present, there is no generally accepted, unified idea of the biologic mechanisms which underlie the development of neoplastic disease.  Whatever the fundamental cellular changes in carcinogenesis are, certain observations can be made about the process. Carcinogenesis usually is a multi-step process, dose dependent and cumulative. In an attempt to explain the mechanisms involved, several theories have been proposed and will be considered here.

Somatic mutation theory

This theory explains that damage to DNA leads to transformation that is heritable and is passed from one cell generation to the next. Evidences for this theory include the finding that most carcinogens are mutagens, radiation act this way, some tumours are hereditary and therefore genome can code for malignancy, and oncogenic virus insert their genome before they can cause transformation. Of all the theories, this theory is widely accepted.

Oncogene theory

It has been proposed that all cells (somatic and germ cells) contain latent oncogene from oncogenic viruses which are activated by a variety of external insults to produce transforming substances. Supporting evidence includes the finding that oncogene sequences can be found in nearly all cells from all creatures. It suffered from the basic unexplained fact that tumours induced by oncogenic viruses contain specific antigens in neoplastic cell surfaces while those produced by chemicals do not have this antigen.

Epigenetic theory

This theory considers that all cells contain the complete genome capable of producing the characteristics of a malignant cell. Derepression of genes through alterations of cytoplasmic proteins leads to differentiation to a fetal cell type. Supporting evidences include the findings that even the most malignant feature (invasion and metastasis) do occur in normal cells (e.g. trophoblast extension, leucocyte migration); not all carcinogens are mutagens but can bind to proteins as well as DNA and RNA; Derepression of normal genes results to expression of fetal products (onco-fetal antigens); and transformation proceeds in stages not as an all or none phenomenon as expected for a genetic mutation. This theory is widely accepted.

 FACTORS INFLUENCING CARCINOGENESIS

The factors that influence carcinogenesis include the following:

1] Environment/Geographic factors - related to exposure of animals to carcinogens (e.g. exposure of cattle to sites with bracken fern and prolonged intake may lead to bladder neoplasm; high incidence of sunlight associated with skin cancer in cats, cattle and humans)

2] Sex - the presence (or absence) of susceptible tissues and sex hormones influences carcinogenesis (e.g. mammary tumours are rare in male animals; perianal gland tumours are common in male dogs than in bitches)

3] Hormones - prolonged hormonal stimulation may predispose the target tissue to undergo transformation or susceptible to carcinogenesis (e.g. cyclic hormonal stimulation of mammary gland predisposes to cancer)

4] Breed and hereditary factors - certain breeds have predisposition to tumour growths (e.g. Boxers are notorious for developing all kinds of tumours; Haemangiosarcomas are most common in German Shepherd; Osteosarcomas in large breed of dogs as Great Danes, Irish Wolfhound)

5] Nutrition - related to dietary exposures (e.g. in man, low fibre diet predisposes to colonic carcinoma; exposure to aflatoxin in diet may lead to liver tumours)

6] Age - tumours increases with increasing age, and may be related to the accumulation of somatic mutations or epigenetic events; altered cellular metabolism with age; long latency of carcinogenesis; and decreased immune competence with age.
7] Immunity -  The role played by the immune system in tumour rejection and/or enhancement is still an area of debate. While the immune system may modulate the onset and development of tumours (e.g. increased tumour risk in immunosuppressed animals), there are no proven immune-mediated cures.

While tumour cells, in process of transformation, acquire a different surface antigen that normally provokes an immune reaction, this does not usually happen for some still unknown phenomena. Although spontaneous tumour cells rejections were noted in some tumours in animals (e.g. canine cutaneous histiocytomas, and canine transmissible venereal tumours), there are instances where the immune system fails to recognise tumour cells as foreign to the host. This could be explained by known immunologic phenomena as follows:

[a] Blocking antibodies coat the tumour cells and prevent T cell recognition;

[b] Soluble tumour antigens blocks the specific receptors required for immune recognition;

[c] Tumour cell surface antigens may be poorly immunogenic

[d] Tumour cell secretions may be immunosuppressive

[e] Tumour cell secretions may induct T-cell suppressor system (T-suppressor cells modulate immune reactivities)