Neoplasia
Not all masses are true neoplasms.
Examples of tumors that are not true neoplasms: Hamartoma and Choristoma.
Hamartoma and choristoma are developmental or congenital malformations.
Hamartoma is a mass that consists of tissues that are normally present in the
site of the mass but the organization, or the amount of cells and tissues at that
site is different from the normal situation.
Example of hamartoma: Lung Hamartoma (Pulmonary Hamartoma)
Lung Hamartoma is a mass that consists mainly of mature cartilage with other
components such as respiratory epithelium, stroma and connective tissue.
Cartilage is found normally in the lung in the bronchial tree and the trachea
contains cartilage rings, the cartilage preserves the potency of the bronchial tree
and prevents it from closing. The terminal bronchioles (lung tissue) contain a
small amount of cartilage, so a mass of cartilage with a few centimeters size is
the tumor.
Choristoma is a congenital anomaly, tissues of choristoma are not normally
present in the site where choristoma happens (where the mass is formed).
Pancreatic tissue is found in the pancreas, but if a mass of pancreatic tissue is
found in the wall of the stomach it forms a mass that is called choristoma and it
is also called pancreatic heterotopia (Heterotopic pancreatic tissue is in a
foreign place).
Another example of choristoma: Meckel’s diverticulum. At the end of the small
intestine in the terminal ileum) some patients might have developmental
anomalies which contain gastric mucosa (here the presence of gastric mucosa
is abnormal as it forms a mass and this mass is called choristoma) so there is an
ectopic gastric mucosa in that area.
Hamartoma and Choristoma are not true neoplasms, they do not become
malignant, i.e do not transform into malignancy.
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How to differentiate between benign and malignant
tumors:
1. Differentiation and anaplasia.
2. Rate of growth of the tumor.
3. Presence of capsules around the tumor.
4. Local invasion.
5. Distant metastasis.
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-The uterus is a common site for tumors. Tumors that are found in the uterus are
called fibroid:
If the tumor is benign, surgeons can remove the tumor alone.
But if the tumor is malignant, the whole uterus is removed. Also, if there are
numerous tumors that cause distortion, the whole uterus is removed even if it’s
not malignant.
Different types of tumors in the uterus according to the above Picture:
The tumor on the left side is:
1- smaller in size
2- has a slow growth rate
3- has clear, regular, and well defined borders
4- Has a homogenous appearance
5- well demarcated
6- doesn’t cause invasion to the surrounding tissue
7-doesn’t cause any damage to the blood vessels
8- doesn’t cause necrosis or hemorrhage and has a uniform cut surface.
The tumor on the right side is:
1- larger
2- has a rapid growth rate
3- it invades the surrounding myometrium and endometrium
5- it is variable in appearance and contains variations in the shape and
color: (includes brown and red colors, the brown color indicates necrosis, and
the red color indicates hemorrhage, it poorly demarcated, causes local invasion
and has the ability to metastasize.
The histologic appearance of the tumor on the left is very similar to the
microscopic appearance of the normal smooth muscle (the tumor is very close
to the normal appearance and the differentiation level is high).
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On the other hand, histologic appearance of the tumor on the right contains
hemorrhage and necrosis, some of the cells are similar to the normal smooth
muscle and other cells are rounded with larger nuclei and prominent nucleoli
(these cells look different from the normal smooth muscle cells) and there is a
variation in the level of differentiation, where some of the cells are well
differentiated while other cells (the majority) are not well (poorly) differentiated.
The tumor on the right (malignant) is less differentiated than the tumor on the left
(benign).
Fibroid is not a scientific medical pathological term so:
The tumor on the left side is called leiomyoma.
The tumor on the right side is called leiomyosarcoma.
- Hemorrhage and necrosis are not major distinguishing points but they
help to differentiate between the two types of tumors
- The major two points to differentiate between benign and malignant
tumors is the ability to invade and the ability to metastasize.
Differentiation:
Differentiation indicates how much the cells are similar to the normal cells in
terms of morphology and functionality.
Examples of Differentiation:
1-Functional Differentiation:
A tumor produces a hormone that is exactly similar to the hormone produced by
the normal cells of the organ(Example: Insulin)
2-Morphological Differentiation:
Lipoma cells look very similar to the normal fat cells, this is a morphological
differentiation.
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The yellow mass in the above picture is removed from a superficial part of the
body and it is covered by a capsule (looks shiny in the picture) and it has regular
borders.(Regular borders means it’s benign)
The picture in the bottom left is the section that is taken from the mass:
-Well differentiated mass, the cells are very similar to fat cells.
When studying this mass under low magnification, it is noticed that it consists of
lobules of mature adipocytes, these lobules indicate that this is a neoplasm (it is
benign and more specifically lipoma).
Differences between lipoma and liposarcoma:
1-Nuclei:
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-The nuclei in the liposarcoma cells are more obvious than in the lipoma.
Because the liposarcoma fat cells contain multiple small vacuoles that maintain
the nucleus in the center and it appears more obvious and hyperchromatic.
(Hyperchromatic: stains more darkly than normal nuclei)
-Lipoma Benign or normal fat cells contain a single large vacuole in each cell
that causes expansion and pushes the nucleus to the periphery. (the nucleus
becomes invisible).
2- Cell Size Variety:
Liposarcoma fat cells are diverse in size. (Some cells are large and some are
small).
3- Presence of Lipoblasts in Liposarcoma:
Another indication of liposarcoma is the presence of lipoblasts which are
mature fat cells that contain multiple vacuoles and a large hyperchromatic
nucleus that can be in the center or toward the periphery.
4- Level of Differentiation:
-Lipoma cells are very well differentiated. They are almost identical to the normal
cells.
-Liposarcoma cells varies in differentiation. May be well, moderately or poorly
differentiated or undifferentiated. We may know that these are from a fat tissue.
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benign then it is called papilloma and if it is malignant then it is called
squamous cell carcinoma.
2. Connective tissue cells:
- If a mass of connective tissue cells produces a cartilage matrix then this is an
indication of cartilaginous differentiation.
-The production of osteoid matrix indicates bone differentiation.
-The presence of lipoblasts indicates fatty differentiation.
-The presence of cells that contain striations of the cytoplasm indicates skeletal
muscle differentiation.
The top picture on the left is a section taken from a normal organ where the
epithelial cells form glands (glandular or columnar differentiation).
Pictures 1, 2 and 3 are epithelial tissues (neoplasms) that form glands.
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In picture 1: All the structures are forming glands that contain secretions and
the differentiation level is high (well differentiated).
In picture 2: there is formation of glands (columnar cells forming glands) but
part of the tissue appears solid and some glands have stratified cells and they
are uglier than other cells. Some of the cells are similar to the normal columnar
cells and other cells have a morphological appearance deviated from the normal
cells but in general these cells form glands in a high percentage. This is a
moderately differentiated neoplasm.
In picture 3: There is no formation of glands. All the cells that form the tumor in
the picture are abnormal (they have an abnormal and prominent nucleus) but
some of these cells (pointed with the arrows) contain a good amount of
cytoplasm and contain mucin, the presence of mucin indicates that there is a
columnar(glandular) differentiation in this tissue. This tumor is invasive and it is
called adenocarcinoma. This tumor is poorly differentiated NOT
undifferentiated. (characteristics of undifferentiated:no gland formation, no
squamous arrangement, no keratin formation).
The cells that produce mucin are called signet-ring cells because look like a
ring.
Dysplasia
When a tumor cell loses differentiation, it gradually gains features of dysplasia.
(Dysplasia is related to differentiation).
Dysplasia is mainly used with the epithelium more than other organs and the
main example is the squamous epithelium. Dysplasia is related to changes in the
epithelium, these changes are limited to the epithelial surface and not developed
to cancer or carcinoma.
Dysplasia is a disorderly, non-neoplastic proliferation of cells with loss of
architectural orientation.
Disorderly: no arrangement.
Non-neoplastic:in an earlier stage and not developed in a tumor or cancer.
Dysplasia involves the squamous epithelium found in:
1. The metaplastic squamous epithelium in the lungs as a result of smoking.
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2. The squamous epithelium of the skin.
3. The squamous epithelium of the exocervix (the outer part of the uterus
cervix).
If there is proliferation of the cells in the epithelium with changes in the
arrangement and the shape of the cells and the cells gain specific features this
will cause dysplasia.
- Metaplasia is reversible and if the smoking is stopped the lung goes back
to its normal state of columnar epithelium, but if the dysplasia stage is
reached, it can not go back to normal or progress to an even more
abnormal state even if the smoking is stopped (so if you stop smoking in
the dysplasia stage you can get benefits and sometimes you can’t
because of mutations).
Dysplasia cells are either:
1. Differentiated cells that went through maturation then the maturation
process is reversed so they lose the features of differentiation (there is a
process of gradual loss of differentiation of mature cells) or
2. they are stems cells of the epithelium that gained features other than the
normal features (tumor stem cells).
Dysplasia may precede malignancy.
Total loss of differentiation is called severe dysplasia
Severe Dysplasia = Anaplasia
Example of Severe Dysplasia/Anaplasia:
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The cells in this picture are different from each other.
The nuclear sizes and shapes are variable (pleomorphism).
The colors of the nuclei are different (light,
slightly dark, much darker).
The darker the nucleus is, the higher the level of
hyperchromatism.
The presence of abnormal mitosis (tripolar mitosis).
Mitosis (normal proliferation) can be found in the basal layer of any squamous
epithelium and in the glands of the intestine (specifically colon glands). These
tissues have continuous capacity of regeneration in cases of inflammation,
damage or injuries.
Abnormal mitosis is an indication of dysplasia or a tumor.
In the picture above, in the tumor there is no keratin, mucin or gland formation
and there isn’t any osteoid matrix or cartilage matrix and it is not possible to
determine the origin (site) of the tumor so it is severe dysplasia.
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This picture is a section of squamous epithelium of the cervix with the
underlying subepithelial tissue.
In the right side, there is hyperchromatism, the cells are more crowded, the
nucleus size in increased (so the nuclei are larger and closer to each other) also
mitosis can be noticed above the basal layer (mitosis must be in the basal layer)
and some cells have prominent nucleoli.
● In the top part of normal squamous epithelium, squamous cells with
large nuclei and heavily staining cytoplasm should not be found.
Also in the right side the cells have lost their polarity.
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In the normal squamous epithelium, the basal layer is more primitive and it can
produce mitosis and regenerate. Moving towards the surface, the nucleus
becomes smaller, the cytoplasm increases and the squamous epithelial cells
become arranged above each other.
So the right side of the picture is Dysplasia while the left side is almost normal.
Intraepithelial Neoplasia:
Intraepithelial Neoplasia: Dysplasia involving an epithelial surface.
(In general Dysplasia happens mainly in the epithelial surfaces but it can happen
in connective tissues).
Dysplasia of the epithelial surface is divided into low grade and high grade.
High grade dysplasia is severe dysplasia (anaplasia) that is still limited by the
epithelial basement membrane and it is also called Carcinoma In Situ.
Carcinoma In Situ: Severe dysplasia involves the entire thickness of the
epithelium, but it is not invasive, so it doesn’t cross or attack the basement
membrane and the abnormal cells are kept in the epithelium.
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This picture represents full thickness dysplasia from the basal layer to the top
part. (High grade Intraepithelial Neoplasia)
Dysplasia is divided into high grade and low grade and it can also be divided
into mild, moderate and severe.
- If the dysplasia is in the cells in the lower third of the squamous
epithelium, this is mild dysplasia.
- If the dysplasia involves two thirds, this is moderate dysplasia
- If the dysplasia involves three thirds (full thickness), this is severe
dysplasia (Carcinoma In Situ).
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The right and left sides of the picture above are Carcinoma In Situ (full
thickness dysplasia) but in the middle the basement membrane has been
broken by some of the tumor cells and the tumor has invaded the
subepithelial cells.
The picture above is an example of invasive cancer, there are islands of
squamous epithelial cells that are invading the subepithelial tissue (dysplasia
has broken the basement membrane and moved through to cause invasion
to the underlying tissue).
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Dysplasia features can occur in both Carcinomas and Sarcomas b ut there
is no In-Situ Sarcoma. (Dysplasia term can be used in the epithelium and
connective tissue abnormal proliferation but Carcinoma In-Situ term is used
in the epithelial dysplasia but there is no In-Situ Sarcoma because the
connective tissue doesn’t have a basement membrane).
Not all dysplasias progress to higher grade or Carcinoma In Situ.
Not all Carcinoma In Situ progress to invasive Carcinoma, although they have a
high chance of doing so.
(For example: Dysplasia in the squamous epithelium of the lung, if the smoking
is stopped the dysplasia might remain in the same stage or it might progress
back or progress to cancer).
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The tumor growth rate.
The general rule: Usually slow in benign and rapid in malignant tumors.
The rate of growth usually correlates with level of differentiation.
Benign neoplasm is usually well differentiated.
The growth rate is important in malignant neoplasms because they are divided
into different levels of differentiation, and the rate of growth depends on the
differentiation level, when the level of differentiation increases the tumor grows
more rapidly.
Exceptions:
(Exceptions to the general rule)
1. Hormonal influences: e.g Leiomyoma of uterus in pregnancy (hormones
may cause the benign to grow more rapidly).
2. Pressure constraints: (when a tumor grows in an organ or a site that is
confined by an anatomic border, for example in the brain the pituitary
gland is surrounded by a bone, this bone prevents the free growth of the
tumor and can also cause pressure on the blood supply which can cause
necrosis even if the tumor is benign).
3. Some malignant tumors may outgrow their blood supply.
(C. Ischemic n.)
Some tumor growths are hormone – dependent:
These tumors need hormones to grow.
Examples: - Breast cancer
- Endometrial cancer
- Prostatic cancer
* There are many types of breast cancers and the majority of these types
depend on the hormone estrogen and also progesterone, so these tumors have
receptors for estrogen.
* Prostate cancer depends on the hormone testosterone.
* Endometrial cancer depends on the hormone estrogen.
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- Endometrial hyperplasia is a response to an endogenous source
or exogenous source of extra estrogen, endometrial hyperplasia can develop
into endometrial carcinoma.
The effect of hormones is very important in the management of tumors: certain
drugs were developed for tumors that depend on hormones, these drugs attach
to the hormone receptors to block them.
Examples: In case of breast cancer, anti-estrogen drugs are used.
In case of prostate cancer, one of the treatment ways is to remove the patient’s
testicles to reduce the testosterone levels and this may cause a shrinkage in the
size of the cancer.
So the hormone therapy relies much on this phenomena.
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Metastasis: Spread of malignant tumors to distant sites away from the main
tumor.
The ability to have distant spread is a feature of malignant neoplasm not benign.
(this is the general rule and there are some exceptions)
For example: a bone tumor that moves to the lung is a malignant tumor.
Metastasis is proportionate to the size and to the degree of differentiation of the
primary tumor.
When the differentiation decreases, this increases the risk of having a malignant
tumor that is able to metastasize.
All malignant tumors can potentially metastasize except B asal cell carcinoma
and Most primary brain tumors (both can have local invasion and rarely can
metastasize).
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