This abnormal growth usually but not always forms a mass.

The World Health Organization classifies neoplasms into four main groups: benign neoplasms, in

situ neoplasms, malignant neoplasms, and neoplasms of uncertain or unknown behavior. A malignant

neoplasm is a cancer. Prior to abnormal growth, cells often undergo

an abnormal pattern of growth, such as metaplasia or dysplasia. However, metaplasia or dysplasia

do not always progress to neoplasia. The growth of neoplastic cells exceeds, and is not coordinated

with, that of the normal tissues around it. The growth persists in the same excessive

manner even after cessation of the stimuli. It usually causes a lump or tumor.

In modern medicine, the term tumour means a neoplasm that has formed a lump. In the

past, the term tumour was used differently, referring to a lump of any cause. Some neoplasms

do not cause a lump.

Types A neoplasm can be benign, potentially malignant,

or malignant. Benign neoplasms include uterine fibroids

and melanocytic nevi. They are circumscribed and localized and do not transform into cancer.

Potentially malignant neoplasms include carcinoma in situ. They do not invade and destroy but,

given enough time, will transform into a cancer. Malignant neoplasms are commonly called cancer.

They invade and destroy the surrounding tissue, may form metastases and eventually kill the

host. Secondary neoplasm refers to any of a class

of cancerous tumor that is either a metastatic offshoot of a primary tumor, or an apparently

unrelated tumor that increases in frequency following certain cancer treatments such as

chemotherapy or radiotherapy. Definition

Because neoplasia includes very different diseases, it is difficult to find an all-encompassing

definition. The definition of the British oncologist R.A. Willis is widely cited: "A

neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated

with that of the normal tissues, and persists in the same excessive manner after cessation

of the stimulus which evoked the change." This definition is criticized because some

neoplasms, such as nevi, are not progressive. Clonality

Neoplastic tumors often contain more than one type of cell, but their initiation and

continued growth is usually dependent on a single population of neoplastic cells. These

cells are presumed to be clonal – that is, they are descended from a single progenitor

cell. Sometimes, the neoplastic cells all carry

the same genetic or epigenetic anomaly that becomes evidence for clonality. For lymphoid

neoplasms, e.g. lymphoma and leukemia, clonality is proven by the amplification of a single

rearrangement of their immunoglobulin gene or T-cell receptor gene. The demonstration

of clonality is now considered to be necessary to identify a lymphoid cell proliferation

as neoplastic. It is tempting to define neoplasms as clonal

cellular proliferations but the demonstration of clonality is not always possible. Therefore,

clonality is not required in the definition of neoplasia.

Neoplasia vs. tumor Tumor originally meant any form of swelling,

neoplastic or not. Current English, however, both medical and non-medical, uses tumor as

a synonym of neoplasm. Some neoplasms do not form a tumor. These

include leukemia and most forms of carcinoma in situ.

A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size.Tumor

is not synonymous with cancer. While cancer is by definition malignant, a tumor can be

benign, pre-malignant, or malignant. The terms "mass" and "nodule" are often used

synonymously with "tumor". Generally speaking, however, the term "tumor" is used generically,

without reference to the physical size of the lesion. More specifically, the term "mass"

is often used when the lesion has a maximal diameter of at least 20 millimeters in greatest

direction, while the term "nodule" is usually used when the size of the lesion is less than

20 mm in its greatest dimension. Causes

A neoplasm can be caused by an abnormal proliferation of tissues, which can be caused by genetic

mutations. Not all types of neoplasms cause a tumorous overgrowth of tissue, however.

Recently, tumor growth has been studied using mathematics and continuum mechanics. Vascular

tumors are thus looked at as being amalgams of a solid skeleton formed by sticky cells

and an organic liquid filling the spaces in which cells can grow. Under this type of model,

mechanical stresses and strains can be dealt with and their influence on the growth of

the tumor and the surrounding tissue and vasculature elucidated. Recent findings from experiments

that use this model show that active growth of the tumor is restricted to the outer edges

of the tumor, and that stiffening of the underlying normal tissue inhibits tumor growth as well.

Benign conditions that are not associated with an abnormal proliferation of tissue can

also present as tumors, however, but have no malignant potential. Breast cysts are another

example, as are other encapsulated glandular swellings.

Encapsulated hematomas, encapsulated necrotic tissue, keloids and granulomas may also present

as tumors. Discrete localized enlargements of normal

structures due to outflow obstructions or narrowings, or abnormal connections, may also

present as a tumor. Examples are arteriovenous fistulae or aneurysms, biliary fistulae or

aneurysms, sclerosing cholangitis, cysticercosis or hydatid cysts, intestinal duplications,

and pulmonary inclusions as seen with cystic fibrosis. It can be dangerous to biopsy a

number of types of tumor in which the leakage of their contents would potentially be catastrophic.

When such types of tumors are encountered, diagnostic modalities such as ultrasound,

CT scans, MRI, angiograms, and nuclear medicine scans are employed prior to biopsy and/or

surgical exploration/excision in an attempt to avoid such severe complications.

The nature of a tumor is determined by imaging, by surgical exploration, and/or by a pathologist

after examination of the tissue from a biopsy or a surgical specimen.

Malignant neoplasms DNA damage

DNA damage is considered to be the primary underlying cause of malignant neoplasms known

as cancers. Its central role in progression to cancer is illustrated in the figure in

this section, in the box near the top. DNA damage is very common. Naturally occurring

DNA damages occur at a rate of more than 60,000 new damages, on average, per human cell, per

day [also see article DNA damage ]. Additional DNA damages can arise from exposure to exogenous

agents. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the

likely cause of lung cancer due to smoking. UV light from solar radiation causes DNA damage

that is important in melanoma. Helicobacter pylori infection produces high levels of reactive

oxygen species that damage DNA and contributes to gastric cancer. Bile acids, at high levels

in the colons of humans eating a high fat diet, also cause DNA damage and contribute

to colon cancer. Katsurano et al. indicated that macrophages and neutrophils in an inflamed

colonic epithelium are the source of reactive oxygen species causing the DNA damages that

initiate colonic tumorigenesis. Some sources of DNA damage are indicated in the boxes at

the top of the figure in this section. Individuals with a germ line mutation causing

deficiency in any of 34 DNA repair genes are at increased risk of cancer. Some germ line

mutations in DNA repair genes cause up to 100% lifetime chance of cancer. These germ

line mutations are indicated in a box at the left of the figure with an arrow indicating

their contribution to DNA repair deficiency. About 70% of malignant neoplasms have no hereditary

component and are called "sporadic cancers". Only a minority of sporadic cancers have a

deficiency in DNA repair due to mutation in a DNA repair gene. However, a majority of

sporadic cancers have deficiency in DNA repair due to epigenetic alterations that reduce

or silence DNA repair gene expression. For example, for 113 sequential colorectal cancers,

only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced

MGMT expression due to methylation of the MGMT promoter region. Five reports present

evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to

methylation of the MGMT promoter region. Similarly, out of 119 cases of mismatch repair-deficient

colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in

6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient

because its pairing partner MLH1 was repressed due to promoter methylation. In the other

10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA,

miR-155, which down-regulates MLH1. In further examples [tabulated in the article

Epigenetics], epigenetic defects were found at frequencies of between 13%-100% for the

DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1

and ATM. These epigenetic defects occurred in various cancers. Two or three deficiencies

in expression of ERCC1, XPF and/or PMS2 occur simultaneously in the majority of the 49 colon

cancers evaluated by Facista et al. Epigenetic alterations causing reduced expression of

DNA repair genes is shown in a central box at the third level from the top of the figure

in this section, and the consequent DNA repair deficiency is shown at the fourth level.

When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher

than normal level, and these excess damages cause increased frequencies of mutation and/or

epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair

or in homologous recombinational repair. During repair of DNA double strand breaks,

or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic

gene silencing. DNA repair deficiencies cause increased DNA damages which result in increased

somatic mutations and epigenetic alterations. Field defects, normal appearing tissue with

multiple alterations, are common precursors to development of the disordered and improperly

proliferating clone of tissue in a malignant neoplasm. Such field defects may have multiple

mutations and epigenetic alterations. Once a cancer is formed, it usually has genome

instability. This instability is likely due to reduced DNA repair or excessive DNA damage.

Because of such instability, the cancer continues to evolve and to produce sub clones. For example,

a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, demonstrating tumour

heterogeneity, 59 mutations shared by some, and 29 “private” mutations only present

in one of the areas of the cancer. Field defects

Various other terms have been used to describe this phenomenon, including "field effect",

"field cancerization", and "field carcinogenesis". The term “field cancerization” was first

used in 1953 to describe an area or “field” of epithelium that has been preconditioned

by largely unknown processes so as to predispose it towards development of cancer. Since then,

the terms “field cancerization” and “field defect” have been used to describe pre-malignant

tissue in which new cancers are likely to arise.

Field defects are important in progression to cancer. However, in most cancer research,

as pointed out by Rubin “The vast majority of studies in cancer research has been done

on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence

that more than 80% of the somatic mutations found in mutator phenotype human colorectal

tumors occur before the onset of terminal clonal expansion. Similarly, Vogelstein et

al. point out that more than half of somatic mutations identified in tumors occurred in

a pre-neoplastic phase, during growth of apparently normal cells. Likewise, epigenetic alterations

present in tumors may have occurred in pre-neoplastic field defects.

An expanded view of field effect has been termed "etiologic field effect", which encompasses

not only molecular and pathologic changes in pre-neoplastic cells but also influences

of exogenous environmental factors and molecular changes in the local microenvironment on neoplastic

evolution from tumor initiation to patient death.

In the colon, a field defect probably arises by natural selection of a mutant or epigenetically

altered cell among the stem cells at the base of one of the intestinal crypts on the inside

surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby

stem cells by natural selection. Thus, a patch of abnormal tissue may arise. The figure in

this section includes a photo of a freshly resected and lengthwise-opened segment of

the colon showing a colon cancer and four polyps. Below the photo there is a schematic

diagram of how a large patch of mutant or epigenetically altered cells may have formed,

shown by the large area in yellow in the diagram. Within this first large patch in the diagram,

a second such mutation or epigenetic alteration may occur so that a given stem cell acquires

an advantage compared to other stem cells within the patch, and this altered stem cell

may expand clonally forming a secondary patch, or sub-clone, within the original patch. This

is indicated in the diagram by four smaller patches of different colors within the large

yellow original area. Within these new patches, the process may be repeated multiple times,

indicated by the still smaller patches within the four secondary patches which clonally

expand, until stem cells arise that generate either small polyps or else a malignant neoplasm.

In the photo, an apparent field defect in this segment of a colon has generated four

polyps. These neoplasms are also indicated, in the diagram below the photo, by 4 small

tan circles and a larger red area. The cancer in the photo occurred in the cecal area of

the colon, where the colon joins the small intestine and where the appendix occurs. The

fat in the photo is external to the outer wall of the colon. In the segment of colon

shown here, the colon was cut open lengthwise to expose the inner surface of the colon and

to display the cancer and polyps occurring within the inner epithelial lining of the

colon. If the general process by which sporadic colon

cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed

by formation of internal sub-clones within the initial clone, and sub-sub-clones inside

those, then colon cancers generally should be associated with, and be preceded by, fields

of increasing abnormality reflecting the succession of premalignant events. The most extensive

region of abnormality would reflect the earliest event in formation of a malignant neoplasm.

In experimental evaluation of specific DNA repair deficiencies in cancers, many specific

DNA repair deficiencies were also shown to occur in the field defects surrounding those

cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer

was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which

the same epigenetically caused DNA repair deficiency was found in the surrounding field

defect. Some of the small polyps in the field defect

shown in the photo of the opened colon segment may be relatively benign neoplasms. Of polyps

less than 10mm in size, found during colonoscopy and followed with repeat colonoscopies for