Neoplasia Khairat battah, MD University of jordan Faculty of medicine, pathology department.

-Neoplasia literally means "new growth“ -In medicine it is referred to as a tumor, -The study of tumors is called oncology.

fundamental and shared characteristics of cancers: Cancer is a genetic disorder caused by DNA

mutations that are (for the most part) acquired spontaneously or induced by environmental insults.

Genetic alterations are heritable Accumulation of mutations gives rise to a

set of properties that have been called hallmarks of cancer. 

-Neoplastic cells are transformed because they continue to replicate, independent of normal regulatory mechanisms, so enjoy a certain degree of autonomy.

-But their autonomy is not complete, because they

depend on the host for their nutrition and blood supply.

-Neoplasms are either benign or malignant.

-All tumors, benign and malignant, have two basic components:

1 .The neoplastic cells (the parenchyma) which determines its biologic behavior ,

2 .The non-neoplastic connective tissue stroma, is important to the growth of the neoplasm

In general, benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises.

I. Benign mesenchymal Tumors:

a. A benign bone tumor is called osteomab. A benign smooth muscle tumor is leiomyoma

Nomenclature

II. Benign epithelial tumors

1 .Adenomas : Are benign epithelial neoplasms producing glands or derived from glands such as renal adenomas and adenomas derived from adrenal cortex.

2 .Polyp : Is a mass projects above a mucosal surface, as in gut. Most polyps are benign adenomas but a few are malignant .

3 .Cystadenomas : like cystic tumors that arise in the ovary

4 .Papillomas are benign epithelial neoplasms, growing on any surface, that produce microscopic or macroscopic finger-like fronds.

Teratoma:

Is a tumor contains tissues (either mature or immature) from more than one germ cell layer and sometimes all three layers, and present in ovaries and testes.Contain bone, epithelium, muscle, fat, nerve.

III. Malignant mesenchymal neoplasms -Malignant neoplasms arising in “solid”

mesenchymal tissues or its derivatives are called sarcomas

-Malignant neoplasms arising from the mesenchymal cells of the blood are called leukemias or lymphomas -

IV. Malignant tumors of epithelium are carcinomas -Those arise from glands adenocarcinomas

-Those produce squamous cells called squamous cell carcinomas

-Poorly differentiated or undifferentiated carcinoma

Choristoma called (heterotopia) -Is a congenital anomaly not a neoplasm.

-Means presence of normal tissue in an abnormal location such as presence of normal pancreatic tissue in stomach.

Misnomers

Hamartoma is a malformation that presents as a mass of disorganized tissue  native to the particular site.

Not a neoplasm.- Example : hamartomatous nodule in the lung

containing islands of cartilage, bronchi, and blood vessels

Misnomers

A. Differentiation and anaplasia Diffrentiation means how much neoplastic cells resemble their

normal forebears morphologicaly and functionaly

1 .Benign neoplasms : Composed of well-differentiated cells that resemble their normal counterparts.Example: Lipoma and chondroma.

2 .Malignant neoplasms: Characterized by a wide range of differentiation, from well differentiated to poorly

differentiated. .

CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS

The better the differentiation of the cell, the more completely it retains the functional capabilities found in its normal counterparts.

Benign neoplasms and even well-differentiated cancers of endocrine glands frequently elaborate the hormones characteristic of their origin.

Well-differentiated squamous cell carcinomas elaborate keratin.

Anaplasia means lack of differentiation, is considered a hallmark of malignancy.

Anaplastic cells display: Marked pleomorphism (i.e., marked variation in size and shape) Nuclei are extremely hyperchromatic (darkly stained) and large.. The nuclear-to-cytoplasmic ratio is high. Giant cells . Anaplastic nuclei are variable and bizarre in size and shape. nucleoli may be of astounding size. Mitoses are often numerous and distinctly atypical

B. Rate of Growth -Most benign tumors grow slowly and most cancers

grow faster -The rate of growth of malignant tumors correlates with

their level of differentiation -Poorly differentiated tumors grow more rapidly than

well-differentiated tumors .

-The more rapidly growing and the more anaplastic a tumor, the less likely it is to have specialized functional activity.

C. Local Invasion:1- Benign neoplasms: Usually encapsulated and do not

have the capacity to invade the normal tissue. However, not all benign neoplasms are encapsulated.

2- Cancers grow by progressive invasion, and penetration of the surrounding tissue

- It is necessary to remove a wide margin of surrounding normal tissue after excision of a malignant tumor

Next to the development of metastases, local invasiveness is the most reliable feature that distinguishes malignant from benign tumors.

D. Metastasis :- Are secondary implants of a tumor, discontinuous from

the primary tumor and located in remote tissues - However, not all cancers have ability to metastasize such as basal cell carcinomas of the skin and the majority of malignant central nervous system tumors.

- Approximately 30% of newly diagnosed patients with solid tumors present with clinically evident metastases.- Dissemination strongly may prevent, the possibility of curing the disease.

1-Spread by seeding : Occurs when neoplasms invade a natural body cavity.Examples:1-Ovarian cancer, which spread to the peritoneal surfaces.2-Central nervous system tumors such as medulloblastoma or ependymoma, may penetrate the cerebral ventricles and be carried by the cerebrospinal fluid to reimplant on the meningeal surfaces.

Metastasis occurs by:

2. Lymphatic spread : Is more typical of carcinomas. Enlargement of lymph nodes near primary neoplasm should arouse concern for metastatic spread. However , it does not always imply metastasis. Depends on lymphatic drainage of the organ. Sentinel lymph node is the first regional lymph node that receives lymph flow from a primary tumor.

3 .Hematogenous spread : -Is the favored pathway for sarcomas

-Arteries are penetrated less than veins. -Liver and lungs are the most common site for

hematogenous metastasis. -The skeletal muscles are rarely the site of metastatic

deposits

However, there are numerous interconnections, between the lymphatic and vascular systems, and so all forms of cancer may disseminate through either or both systems

-It contribute to knowledge about the origin of cancer. For example the association between smoking and lung cancer arose from epidemiologic studies

-There is association between high dietry fat and low fiber with colon cancer.

Cancer Epidemiology

1 -Age:The cancer frequency increases with age.

-This is due to accumulation of somatic mutations and the decline in immune competence with age.

-Cancer occurs also among children-The major lethal cancers in children are leukemias, tumors of the

central nervous system, and bone sarcomas..

2 -Geographic and Environmental Variables.

3 -Heredity: -Only 10% of cancers are familial

4-Acquired Preneoplastic Lesions -Increase the likelihood of malignancy, but most do not

progress to cancer and their removal may prevent the development of a cancer.

-Examples.a. Endometrial hyperplasia.b. Cirrhosis. c. villous adenoma of colon.

Are benign tumors precancerous ?-In general the answer is no, but there are exceptions,

and it is better to say that each benign tumor is associated with a particular risk, ranging from high to virtually nonexistent.

-For example, large colon villous adenoma can undergo malignant transformation. However, leiomyomata of uterus do not transform to malignany.

Biology of tumor growth, invasion and metastasis

The tumor cell develop self sufficiency in growth signals as they

use a number of strategies to drive their proliferation and become

insensitive to normal growth regulators. The tumor cell become insensitivity to growth inhibitory signals The tumor cell can evade cell death (apoptosis) The tumor cell have limitless replicative potential The tumor develop sustained angiogenesis

Tumor growth

Development of neovascularization

- Tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized.

- The 1 to 2 mm zone represents the maximal distance across which oxygen and nutrients can diffuse from blood vessels.

Importance of vascularization:

1. It supplies needed nutrients and oxygen,

2. Is required for tumor metastasis

3. Growth factors for tumor growth

The metastatic cascade can be subdivided into two phases:

1- Invasion of extracellular matrix (ECM) and vascular dissemination.2- Homing of tumor cells.

A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane.

Invasion and metastasis

a. Detachment of tumor cells.: due to loss of inter-cellular E-cadherin function that keeps the cells together;

b. Local degradation of the basement membrane and connective tissue.

c. Attachment of tumor cells to ECM.d. Migration of tumor cells: propelling tumor cells through degraded basement membranes and the interstitial connective tissue.

steps of invasion of ECM:

Tumor cells in the circulation are prone to destruction by immune cells .

In the bloodstream, some tumor cells form emboli by aggregating with platelets; thus aggregated tumor cells are afforded some protection from antitumor cells.

Vascular Dissemination and homing:

Extravasation of free tumor cells or tumor emboli involves adhesion to the vascular endothelium, followed by egress through the basement membrane into the organ parenchyma by mechanisms similar to those involved in invasion.

The site of extravasation and the organ distribution of metastases generally can be predicted by the location of the primary tumor and its vascular or lymphatic drainage

1. Chemical Carcinogens A-Diret-Acting Agents: Direct-acting agents require no metabolic conversion to become carcinogenic Weak carcinogens.

Are important because some are cancer chemotherapy drugs (Alkylating agents) used to cure certain lymphoma but can evoke a subsequent, second form of cancer, usually leukemia.

ETIOLOGY OF CANCER :

b. Indirect-Acting Agents: chemicals that require metabolic conversion to

an ultimate carcinogen.1- Benzo[a]pyrene present in cigarette smoking cause

lung cancer.2- Polycyclic hydrocarbons which are produced from smoked meats and fish and fossil fuels.3- Aromatic amines and azo dyes associated with urinary bladder cancer. 4. Aflatoxin B1 produced by Aspergillus, that grows on improperly stored grains and can cause hepatocellular carcinoma.

2. Radiation Carcinogenesis

A- Therapeutic irradiation of the head and neck can give rise to thyroid cancers years later.

B- Natural UV radiation derived from the sun can cause skin cancers .

Cumulative DNA damage is the mechanism of carcinogenesis.

Note: patients with the inherited disease xeroderma pigmentosum

(defective DNA repair), there is a increased predisposition to skin

cancers .

3.Viral and Microbial Oncogenesis

Oncogenic DNA Viruses:

1. Human Papillomavirus (HPV) causes: a. Skin warts. b. Genital warts caused by low risk HPV (6 and 11) c. Squamous cell carcinoma of the uterina cervix caused

by high-risk HPVs (16 and 18)

2. Epstein-Barr Virus (EBV) : a. Burkitt lymphoma b. Lymphomas in patients with AIDS c. Nasopharyngeal carcinoma. d. Hodgkins lymphoma.

3. HBV and HCV :- Hepatocellular carcinoma.

Bacterial agents - H. pylori bacteria may cause

1 .Adenocarcinoma of stomach .2 .Gastric lymphoma (MALT) and early eradication of H.

pylori "cures" the lymphoma. There is an initial development of chronic

inflammation/gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. This sequence takes decades to complete and occurs in only 3% of infected patients.

1 - Oncofetal Antigens: -Such as carcino-embryonic antigen (CEA) and alpha

fetoprotein . -Are expressed during embryogenesis but not in normal adult.

-Although, they are not tumor-specific, they can serve as serum markers for cancer. For example , serum CEA is high in cases of colon cancer.

Tumor Antigens

2 .Cell Type-Specific Differentiation Antigens

-Tumors express molecules that normally are present on the cells of origin and these antigens are called differentiation antigens.

-Such as PSA (prostate specific antigen) in prostate cancer.

Both malignant and benign tumors may cause problems because of

(1) location and impingement on adjacent structures,(2) functional activity such as hormone synthesis or the development of paraneoplastic syndromes,(3) bleeding and infections when the tumor ulcerates through adjacent surfaces, (4) symptoms that result from rupture or infarction(5) cachexia or wasting.

Clinical aspects of neoplasia

1- Location is crucial in both benign and malignant tumors,

a. A small pituitary adenoma can destroy the surrounding normal gland, giving rise to hypopituitarism.

b. Benign and malignant colon tumors can ulcerate and cause hemorrhage and in addition can cause obstruction.

Effects of tumor on host

2. Cancer Cachexia Progressive loss of body fat and lean body mass,

accompanied by weakness, anorexia, and anemia. There is correlation between the size of the tumor and

severity of cachexia Cachexia is not caused by the nutritional demands of

the tumor. Although patients with cancer are anorexic, but

cachexia results from the action of soluble factors rather than reduced food intake; TNF is implicated.

3- Paraneoplastic Syndromes It is the symptom complexes that cannot be explained by local or

distant spread of the tumor or by the elaboration of hormones native to the tissue of origin of the tumor.

Most common syndromes are: Hypercalcemia (PTHrP) Cushing syndrome(ACTH) Nonbacterial thrombotic endocarditis. Occurs in lung, pancreatic and breast cancers and hematologic

malignancies. It should be noted that hypercalcemia resulting from bone

metastases is not a paraneoplastic syndrome.

The grading of a cancerEstablish some estimate of tumor aggressiveness or level of malignancy based on the resemblance of the tumor to the normal tissue (cytologic differentiation) and the number of mitosis.

Staging of cancers is based on :a. The size of the primary lesion,b. The spread to regional lymph nodes ,c. The presence or absence of metastases.

Grading and staging of cancer

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