Neoplasm also commonly referred to as a tumor or tumour is an abnormal growth of tissue.
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
3 years, 25% were unchanged in size, 35% regressed or shrank in size while 40% grew in size.
Genome instability Cancers are known to exhibit genome instability
or a mutator phenotype. The protein-coding DNA within the nucleus is about 1.5% of the
total genomic DNA. Within this protein-coding DNA, an average cancer of the breast or colon
can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be “driver”
mutations, and the remaining ones may be “passenger” mutations However, the average number of DNA
sequence mutations in the entire genome within a breast cancer tissue sample is about 20,000.
In an average melanoma tissue sample the total number of DNA sequence mutations is about
80,000. This compares to the very low mutation frequency of about 70 new mutations in the
entire genome between generations in humans. The high frequencies of mutations in the total
nucleotide sequences within cancers suggest that often an early alteration in the field
defects giving rise to a cancer is a deficiency in DNA repair. The large field defects surrounding
colon cancers were shown by Facista et al. to frequently have epigenetic defects in 2
or 3 DNA repair proteins in the entire area of the field defect. Deficiencies in DNA repair
cause increased mutation rates. A deficiency in DNA repair, itself, can allow DNA damages
to accumulate, and error-prone translesion synthesis past some of those damages may give
rise to mutations. In addition, faulty repair of these accumulated DNA damages may give
rise to epimutations. These new mutations and/or epimutations may provide a proliferative
advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes
do not, themselves, confer a selective advantage, they may be carried along as passengers in
cells when the cells acquire additional mutations/epimutations that do provide a proliferative advantage.
Etymology The term tumor is derived from the Latin "tumere"
to swell. It is similar to the Old French tumour. In the Commonwealth the spelling "tumour"
is commonly used, whereas in the U.S. it is usually spelled "tumor".
In its medical sense it has traditionally meant an abnormal swelling of the flesh. The
Roman medical encyclopedist Celsus described the four cardinal signs of acute inflammation
as tumor, dolor, calor, and rubor. His treatise, De Medicina, was the first medical book printed
in 1478 following the invention of the movable-type printing press.
In contemporary English, the word tumor is often used as a synonym for a cystic growth
or solid neoplasm(cancerous or non-cancerous), with other forms of swelling often referred
to as swellings. Related terms are common in the medical literature,
where the nouns tumefaction and tumescence, are current medical terms for non-neoplastic
swelling. This type of swelling is most often caused by inflammation caused by trauma, infection,
and other factors. Tumors may be caused by conditions other than
an overgrowth of neoplastic cells, however. Cysts are also referred to as tumors, even
though they have no neoplastic cells. This is standard in medical billing terminology.
See also
References