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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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