number - · pdf file-mainly within the abdomen or in the chest. ... -hematogenous pathway is...
TRANSCRIPT
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number 17
Done by Ahmad rawajbeh
Corrected by أسامة الخضر
Doctor Maha shomaf
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In this lecture, we are going to:
complete the differentiation between benign and malignant tumors. -
-start to study the carcinogenic agents.
Local invasion -The presence of infiltration into the surrounding tissues, which is called local
invasion, is a feature for differentiation between malignant and benign tumors.
- Simply, the benign tumor is localized and does not infiltrate into the surrounding
tissues, so local invasion is a unique feature for malignant tumor.
Benign tumors
-The benign tumor does not have the capacity to infiltrate, invade, or metastasize
to distant sites, as do malignant neoplasms.
-Since the bengin tumors grow and expand slowly, they usually develop a rim of
compressed fibrous tissue.
-The benign tumor remains confined to the site of origin and usually surrounded
by a capsule covering the tumor and defining its borders.
This capsule is usually made of fibrous tissue derived from the normal tissue
(stromal cells) around the tumor. the tumor cells are also capable to produce it.
Deposition of the capsule is activated by compression of the parenchymal cells
resulting from the expansion of the growing tumor.
For example: when there is an adenoma in thyroid or endocrine gland, we should
examine the tumor carefully. If we detect any breach in the capsule surrounding
the tumor, we should think of carcinoma.
>>Encapsulation creates a tissue plane that makes the tumor discrete, moveable
(non-fixed), and readily excisable by surgical enucleation.
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Examples: This schwannoma (a benign tumor) arised from a nerve sheath.
You can see that all the tumor was removed and the capsule appears smooth,
shinny, and glistening.
A section from the liver.
You can see a mass covered by a shinny capsule. And if you look at the boundaries
there is a clear cut. So, this tumor is most probably benign(adenoma).
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Oval tumor with clear cut demarcation
A bigger magnification
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There is an important note at the last example:
The concentrated color of the tumor!!
-Hepatocytes produce bile with yellow green color.
-Neoplastic cells lack excretory pathway and they are same as normal hepatocytes
producing bile which abnormally remains within these neoplastic cells. That is why
this tumor has more concentrated color than the surrounding tissue.
Normal parenchymal cells of the liver have excretory pathway so the bile will not
accumulate and give a concentrated color as within the adenoma.
This example represents a resected tumor from the breast.
Remember fibroadenoma is a benign mixed tumor.
The tumor as it looks is defined
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Exceptions:
However, some benign tumor lack the capsule (e.g. leiomyoma of the uterus)
1-Leiomyoma as you know is a benign tumor of smooth muscle origin and it lacks
the capsule but it is still a confined mass and well separated from the surrounding
smooth muscle.
The smooth muscles are usually compressed by the tumor. That is why the
separation well be clear, although there is no any fibrous capsule surrounding the
tumor.
2-Another example is hemangioma which is a benign tumor arises from small
blood vessels.
-It lacks the capsule and the well defined appearance so it has an infiltrative
appearance.
Hemangiomas arise primarily in the skin and in the liver. -
a-liver hemangioma:
-You can see it made up of blood vessels that is why they appear dark in color.
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-This tumor lacks well demarcated boundaries and capsule, as we don’t expect
from a benign tumor.
b-skin hemangioma:
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This section is from skin. There is a clear proliferation of small blood vessels filled
with RBCs and made of thin layer of endothelium.
This tumor is called capillary hemangioma because of the very small blood vessels
There are hemangiomas arising from large blood vessels are called cavernous
hemangiomas
**The lack of the capsule does not mean the tumor is malignant, although
presence of a capsule defines the tumor as benign.
Malignant tumors
The nature of malignant tumors is infiltrative, invasive, and destructive.
So, when we look at the tumor we see that the boundaries are blur and the tumor
invades through the surrounding tissues. That is why we cannot predict really if
the whole tumor is removed after resection.
This is an example of a malignant tumor from the breast (breast carcinoma).
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-This whitish area does not have clear boundaries and invades.
-So after resection, in order to be sure that the complete tumor is removed, we
have to section all the resection margins and examine them under the microscope.
If there are any remaining neoplastic cells in these margins, the surgeon should
take more tissue to ensure that the tumor is totally removed, otherwise the
patient should be given further chemotherapy and there is possibility of
malignancy to occur again.
-The infiltration of slowly growing malignant tumor might not be too clear.
>>However, under the microscope, crab-like penetrative feet appear clearly.
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Metastasis
-Metastasis is the spread of a tumor to sites that are physically discontinuous with the primary tumor.
-By definition benign tumors do not metastasize.
It`s a very unique feature of malignancy -
Without thinking of any other things, if the tumor metastasizes, it is malignant.
-Metastasis is very important. >>Preventing it may have a role in controlling the
tumor and reducing its effects.
-We cannot predict the possibility of metastasis.
>>Two different patients with same malignant tumor might have different
outcomes. One can have quick metastasis and extensive to other organs while the
other might show only limited metastasis.
-However we have now some clues about the possibility and sites of the
secondary.
-First you should remember an example of malignant tumor that is rarely able to
give metastasis, is the basal cell carcinoma of the skin.
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Its behavior is aggressive and invasive locally. It causes destruction of the local
tissue whether it is bone or soft tissue.
**here, there is an evidence that the invasive nature and the ability to metastasize
are separable.
Tumors of the CNS are also locally invasive and rarely give metastasis.
So those are two important exceptions.
In other types of malignant tumor, the metastasis is highly suspected.-
Such as the osteogenic sarcoma that is a tumor of large bones of the lower limb
(the femur and the tibia).
When you have a patient with this tumor you should go and do chest x-ray.
**So, the tendency to metastasize is different from one tumor to another;
however, remember that all malignant tumors do have this ability whether it is
present at the time of diagnosis or is going to develop later on. Even if this feature
does not present initially, metastasis will develop later because the tumor is
developing and growing all the time.
*30% of malignant tumors at the time of the initial diagnosis, they show that they
have metastasis.
*20% of patients have hidden metastasis that is not detected at the time of
diagnosis in the radiological test.
*So 50% of the patients having malignant tumors have metastasis at the time of
diagnosis so metastasis is important to be considered in any patient with
malignant tumor.
-Although Metastasis is unpredictable, there are some clues:
The more anaplastic and larger primary tumor, the more likelihood of having
metastasis.
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So if you have a patient with 10 cm tumor in his colon, the chance is very high for
having metastasis.
There are some cancers do not obey the above rule:-
The choriocarcinoma can send metastasis even If it is very small. So, it is very bad,
and the patient may have widely spread metastasis even if the primary tumor is
not prominent.
Conversely, and there are some large and ominous-looking lesions may not
spread.
pathways of metastasis
• (1) seeding within body cavities.
• (2) lymphatic spread.
• (3) hematogenous spread.
1-Seeding within body cavities.
-Mainly within the abdomen or in the chest.
The most common tumors sending metastasis by this pathway are the ovarian
ones.
Why?
>>Because the ovarian tumor is usually presents at the surface of the ovary and
the tumor cells are loosely adherent cells so the force that keeps these cells
together is lost.
>>The tumor cells detach from the main mass, flow into the abdomen, rest on
the peritoneal surface, and re-grow to form masses.
>>This pathway is characterized by forming multiple small masses that are
present all over the surface which is the peritoneum. That is why this pathway
is called seeding.
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Although, brain tumors are usually doesn’t send metastasis outside the brain,
some of the tumor cells can flow through the CSF (cerebrospinal fluid) and
reach the spinal canal. This occur particularly with tumors that arise close to the
ventricles of the brain or the spinal canal like medulloblastoma and
ependymoma (originate from the lining of the ventricles).
2-Through the lymphatics and veins.
How?
>>They drain the organs of the body. So malignant cells can move from the
primary site to other sites through lymphatics and veins.
>>Lymphatics and veins do have thin walls, that makes traversing across these
walls is easier than the thicker walls of arteries.
-In this pathway, we can predict the organs that are going to have metastatic
tumors.
-In general, carcinomas like to send metastasis through lymphatics while
sarcomas send it through veins (hematogenous pathway).
Lymphatic spread
-For carcinomas, we should check the lymph nodes that enlarge after having
metastatic tumors.
-For example:
>>The lateral half of the breast is drained through the axillary lymph nodes.
So examination of breast mass always should be associated with examination of
the axillary lymph nodes.
If they enlarged, this means that the tumor is already outside the breast and
has metastasized.
-Skip metastases: when metastasis occurs through lymphatics, it is not
necessary to affect all lymph nodes along their way (e.g. metastatic tumor can
develop in the first lymph node, skip the second, and develop in the third.). So
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we have to examine all lymph nodes draining the site in order to detect any
metastasis.
-Sentinel lymph node: the first lymph node that drains the site of a primary
tumor. It might be used by surgeons to see whether the tumor is metastasizing
or not.
A dye is injected at the site of the tumor and the first lymph node receives the
dye is the sentinel lymph node which should be examined later.
-Presence of metastasis in a lymph node is only detected by microscopic
examination. So, while you are at a surgery resecting a tumor, do not forget to
resect the draining lymph nodes and send them for the microscopic
examination.
-The malignant cells may traverse all of the lymph nodes ultimately to reach the vascular compartment by way of the thoracic duct.
Hematogenous spread
In our body we have two venous circulations:
1-Portal venous drainage: passes through the liver.
2-Systemic venous drainage: goes directly into the inferior vena cava.
-The site of the predicted secondary tumors depends on the type of the venous
circulation draining the site of that primary tumor.
e.g. colon malignant tumor cells primarily go to the liver while osteosarcoma
cells of the femur primarily go to the lung.
-That is why it is important to know whether the venous drainage of the organ
having malignancy is systemic or portal.
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-Hematogenous pathway is the most important pathway as the tumor cells
enter the blood and reach different organs in the body.
-Tumors located within organs that are close to the vertebral column are known
to send metastasis to vertebral bones as they share the venous beds with the
vertebra.
This is common to occur with thyroid and prostate tumors.
-Certain tumors can grow within veins this is common with liver and kidney
cancers:
Certain carcinomas have a propensity to grow within veins. The liver tumor can grow within hepatic veins, continue to grow and even reach
the inferior vena cava and causes obstruction.
And the patient may be diagnosed for the first time just for having IVC
obstruction.
Same as kidney tumor that can
grow into the renal vein and might
cause obstruction.
**While hematogenous spread is the
favored pathway for sarcomas,
carcinomas use it as well.
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Etiology of cancer
There are three categories of the underlying causes of tumor.
1-chemicals
2-radiation
3-microbial agents.
Chemical carcinogens:
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They are divided into two main groups:
1-Direct acting chemicals: they are well known as carcinogenic agents because
of their structures.
-They require no metabolic conversion to become carcinogenic. -In general, they are weak.
Used for different studies regarding the cancer. -
2-Indirect acting chemicals: more important because we do not know the
chemical as it is.
-They need to be metabolized into products which are the ultimate
carcinogenic agents.
-They are considered procarcinogens.
Extra Because indirect-acting carcinogens require metabolic
activation for their conversion to DNA-damaging
agents, much interest is focused on the enzymatic pathways
that are involved, such as that mediated by the cytochrome
P-450–dependent monooxygenases. The genes that
encode these enzymes are polymorphic, and enzyme activity
varies among individuals. It is widely believed that the
susceptibility to chemical carcinogenesis depends at least
in part, on the specific allelic form of the enzyme that is
inherited. Thus, it may be possible in the future to assess
cancer risk in a given individual by genetic analysis of enzyme
polymorphisms.
Regarding the tables
Alkylating agents: are used as chemotherapeutic agents and they are widely
used.
-These alkylating agents have the chance to produce secondaries in patients
received these drugs.
>Particularly leukemia and lymphomas.
-These alkylating agents attack the DNA aiming in killing the tumor cells but
they are not selective and hurt normal tissues resulting in a new tumor.
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Acylating agents: chemotherapeutic agents also causing leukemia.
Aromatic hydrocarbons: any chemical containing benzene ring is considered
carcinogen.
-These carcinogens can be uptaken by consumption of tobacco in cigarettes.
-Also, heat can act on animal fats producing aromatic hydrocarbons as in
smoked fish and meat.
Aromatic amides and amines: they dissolve in the blood and induce bladder
cancer.
Beta-naphthylamine is used in rubber and dye industry. -
>>Beta-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily exposed workers in the aniline dye and rubber industries.
Aflatoxin B1: naturally occurring toxin, produced by a fungus
(Aspergillus flavus/ lives in improperly stored grains and nuts), and associated
with liver cancer in African countries because of the early exposure to high
amounts of aflatoxin B1.
>>So liver cancer in Africa occurs in the young age group as it is relative to the
consumption of food.
Betel nuts: in certain areas like in India, people chew this plant which causes
oral carcinoma.
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-Malignant cells should have some mutations in their genes and the chemicals
capable of producing these mutations are considered carcinogens.
-Usually, they share a common feature that is the lack of an electron from the
outer orbital that makes them unstable trying to interact with any site rich in
electrons to gain one electron and go stable.
>>Sites rich in electron like the DNA, RNA, and protein synthesis which is very
important site for cell growth regulation.
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RAS and p53 genes are very important genes. -
RAS initiates cell growth.
P53 controls cell growth.
Carcinogenic chemicals interact with these genes.
Mutations in both genes let the cell start to grow and divide without any
regulatory control leading to malignant formation.
-Chemicals are divided into two types:
Initiator chemicals: initiate or produce genetic mutations on the tumor-
suppressor genes.
However, these cells might stay in the body without forming a tumor. They
need to be exposed to other type of chemicals.
Promoter chemicals: they promote the growth of cells having abnormal genes
Promoters can be anything. They may be enzymes, hormones, coloring agents
in food, etc.
We don’t have a defined list of the promoter chemicals.
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