Outline-Cancer
Cancer is the 2nd leading cause of death in US.
I. Terminology
A. Tumor---swelling—some use it as a neoplasia
B. Neoplasm—new growth-can be benign or malignant
C. Cancer--malignancy
D. Suffix-OMA-indicates swelling (a tumor) but commonly is used to indicate cancers-The two major categories
of cancers are:
1. Carcinoma -epithelial cell origin
2. Sarcoma -connective tissue origin
3. Lymphoma and leukemias are separate.
E. Specific name is usually derived from the tissue where it originates.
1. Ex: Lipoma --benign fatty tumor, and liposarcoma—malignant fatty tumor.
2. Example of non-cancer use—seroma is a collection of serous fluid that is benign
F. Classification: Cancers are classified by gross anatomy, light microscopy, and by molecular characteristics. .
Diagnosis and classification requires a biopsy—a tissue specimen.
G. Staging: depends on size of tumor, local invasion, local spread (lymph nodes), and metastasis. TNM system is
most used. Imaging is often used to identify stages. Staging is important for:
1. Prognosis
2. Therapeutic decisions
3. Accurate discussions
II. Characteristics of Cancers
A. Benign tumors are- localized, demarcated from surrounding normal tissue; well-differentiated; do NOT
invade, destroy or metastasize—but CAN cause symptoms, even death
B. Cancers: can be defined as uncontrolled proliferation of cells
1. poorly differentiated cells (anaplasia)
2. often divide and grow rapidly
3. invade local structures
4. can metastasize
C. Metastasis---spread of cancer cells from original site to a distant site (by lymphatic or blood vessels)
D. Cancer cells compete with normal cells:
1. for space, nutrients including oxygen, and blood supply.
2. Angiogenesis is necessary to allow tumor growth—specific vessel growth factors are produced.
E. For cancer cells to survive, they must have:
1.Immortality
2.unregulated growth-(no rest or repair)
3.avoidance of apoptosis
These have specific genetic or epigenetic changes behind them.
F. Tumor markers-various chemicals associated with some cancers—not very useful for screening as too
imprecise, but have some usefulness in following tumor recurrence, etc.
G. PET (positron-emission-tomography) scans- often cancer cells metabolize glucose more, faster, and through a
different pathway. This uses more glucose than non-cancer cells, the basis for PET scanning.
H. Paraneoplastic syndromes-Cancer cells do NOT function like their cells of origin. BUT some cancer cells
secrete cytokines unrelated to the cells of origin that cause symptoms. Examples are:
1. Some lung cancers secrete a parathormone-like substance that acts like parathormone, so can cause
bone osteoclastic activity and elevated serum calcium levels
2. Neuropathies can be caused by a large variety of cancers
I. Carcinoma-in-situ: abnormal cells do not cross the basement membrane, so it is not invasive and cannot
metastasize (not a “real” cancer). This may or may not progress to invasive cancer.
III. Development of Cancers
A. Age is (often) the biggest risk factor to development of cancer.
B. All cancers must have mutations--- changes in DNA.
1.These changes affect the normal cell cycle—No rest, no repair, no growth inhibitors, no control of
mitosis.
2.The mutated cells escape immune surveillance---not recognized as “Non-Self”, or some other defect
in the immune system prevents the cells from being destroyed
a. The immune system normally does attack cancer cells as “others”
b. Immunosuppression interferes with that protection
C. Carcinogens (nicotine, UV light, radiation, etc.) act by causing mutations in the DNA
D. To develop a cancer, one must have a collection of mutations . There are 3 kinds of genes involved:
1. Concept is-- normal cell-cycle has on- and off-switches—where normal genes have a signal “things
are okay—proceed” or “things are not okay-commit suicide (apoptosis)”
2.Proto-Oncogenes-in normal state, they direct synthesis of proteins that regulate cell proliferation and
tell it to proceed
a. Mutations of these genes are called oncogenes: lose the usual regulation of cell proliferation
and just tell it to proceed
b. May be point mutations—small changes in DNA that have profound effects or
chromosome translocations. (Ex: tyrosine kinase production in CLL)
3. Tumor-suppressor genes-- negatively regulate proliferation -slows or stops it
a. Mutations allow proliferation to proceed with no down-regulation even when it should not
(brakes don’t work)
b. Specific signals can tell proliferation to stop as cell density is high enough (enough in the
neighborhood, so don’t make more)-mutations do not get that signal, or tell cells to stop
production
4. Caretaker genes- responsible for maintenance of genomic integrity. They repair DNA that is damaged
by radiation, ultraviolet light, chemicals, etc. If these genes lose their functions, there are increased
mutation rates.
5. Epigenetic effects
a. often act to silence-or decrease a genetic expression
b. Example: Critical suppressor genes can be turned off without genetic mutation.
E. Sporadic cell mutations vs heritable
1. Most of these genetic changes occur during lifetime, not from inherited genes. (acquired mutations)
they are in somatic cells
2. Heritable mutations are in germ-cells so in every cell in the body
a. There are many recognized mutations in this category (BrCa 1 and 2 are examples)
b. Epigenetic “mutating” effects can be heritable
c. A sporadic mutation may occur in germ cells, and then be heritable
IV. Inflammation and Infection can be Carcinogenic
A. Chronic active inflammation is associated with increased incidences of cancers.
1. Ulcerative colitis increases the incidence of colon cancer by a factor of 30
2. Hepatocellular cancer is much increased when there is chronic hepatitis present (either B or C
hepatitis).
3. It is believed that it is the chronic inflammatory reaction that has these effects. Inflammation
increases cell proliferation, increases free radicals, and more.
B. Infectious agents that increase the incidence of cancer:
1. Examples:
H. pylori
gastric cancer
HIV-1
Kaposi’s sarcoma, lymphoma
Schistosomiasis (a parasite)
bladder, liver and rectal cancers
Hepatitis B and C
hepatocellular cancer
Epstein-Barr
lymphomas
HPV
Cervical (& others) cancer
2. Viral infection is associated with about 15% of all cancers.
3. The chronicity of the inflammation increases incidences. ( 80% of liver cancers are associated with
chronic hepatitis, either Hep B or C).
4. Almost all cervical cancers are associated with HPV. HPV causes cancer when the viral DNA is
integrated into the cellular genomic DNA.
5. Oncogenic viral infections by themselves do NOT cause cancer. They cause one mutation among many
6. Immunosuppressed patients, as in transplant patients, have 10 times the incidence of lymphoma and
1000 times the incidence of Kaposi’s sarcoma. But there is little increase in common tumors (breast,
colon, etc) in those patients.
7. The role of the immune system is complex, as there are factors which increase proliferation of cells,
and factors which decrease it.
V. Cellular stages and Metastasis
A. Steps towards cancer cells
1. metaplasia, dysplasia, carcinoma-in-situ, invasive cancer
2. Each step is non-obligatory—it may be taken (ex: another mutation necessary) or not
B. Steps necessary for metastasis
1. invasion of blood and/or lymphatic vessels
2. Survival in the circulation (again avoiding immune system)
3. Attachment in an appropriate environment—target organs
4. Multiplication there
5. A low percentage of cancer cells in the blood succeed in metastatic development
VI. Clinical Manifestations of Cancer
A. Specific to the cancer: obstruction of GI tract, GU tract; neuro symptoms, liver disorders, etc, etc.
B. Common and non-specific Pain, fatigue, cachexia, anemia.
1. Cytokines from the cancers, and/or from WBC’s attacking them, cause breakdown of fat and muscle.
2. Leukopenia and thrombocytopenia are usually due to chemotherapy but sometimes due to
involvement of bone marrow with the cancer.
C. Infection: a significant cause of complications and death from cancers.
1. White blood cell count decreases (either tumor effects or chemotherapy).
2. Immunosuppression occurs because of the cancer itself and also the therapies.
3. Nosocomial infection in these patients is significantly increased.
VII. Treatments for Cancer
A. Local—surgery, +/- radiation
B. Systemic—chemotherapy, +/- radiation
C. Combined modality—2 or 3 of the above
D. Adjuvant-treating micro-deposits of cancer cells that may or may not be present—treat statistics
E. Targeted therapies
1.Recognition that some mutations are shared by different cancers--2.Example is (some) mutations that turn off tumor-suppressor effects
3.Result is targeted therapy to block that mutation can be used in “many” cancers
4. Monoclonal antibodies
5. Blocking checkpoint inhibitors—designed to overcome the resistance of some tumors to the immune
system
a. Normal immune surveillance identifies tumor cells as non-self and activates T cells to destroy them
b. Successful tumor cells make proteins that block that activation
c. Monoclonal antibodies can be made that block those tumor proteins, so T cell activation persists
6. Drugs to specifically interfere with epigenetic effects—demethylating agents, etc.
VIII. Notes on a few specific cancers
A. Cancers in the USA are decreasing in incidence and mortality
B. This is due to: screening; therapy, and lifestyle changes. And improved treatment
C. Lung cancer
1.Most cancer deaths in the world
2. About 70% of patients present with advanced disease—over 50% have metastases at diagnosis
3. Overall survival 17% at 5 years
4. Average age at diagnosis Is 70 years old
5. Cigarette smoking is present in 90% (11% of heavy smokers get lung cancer)
6. Metastases TO lungs more common than primary cancers
D. Breast cancer
1. about 1 in 8 women—occurs in males also
2. Only 20% patients have a + family history
3. BrCa genes—autosomal dominant—act to make tumor-suppressor genes ineffective
A .Increase risk of pancreas, prostate, and melanoma also
4. Estrogen/Progesterone receptors promote cell division---AND we have treatments
5. Her-2 promotes breast tissue growth—AND we have treatments
6. DCIS—diagnosis increased (mammograms) and treatment difficult
7. Evolution of nodal examination
8. Adjuvant therapy common---overall 5 year survival is 90%
E. Cervical Cancer
1. HPV
a. Nearly 100% of cervical cancers are “caused” by HPV
b. About 5% of females with HPV infection develop cervical cancer
2. PAP smear very useful screening
3. Long history/course---10-15 years to progress from dysplasia to invasive cancer
4. Early stages have a 91% 5-year survival
5. Vaccine against HPV available and efficacious----prevents 90% of new cases
F. Prostate Cancer
1. Very common-6 out of 10 men over 60 years old have this on biopsy
2. Aggressive vs. incidental cancers????
3. PSA-tumor marker –debate about utility in screening
4. Treatment—necessary? If so, which one?
IX. Childhood Cancers
A. More deaths in US children than any other disease
B. 300,000 children diagnosed each year in the world
C. Leukemia, lymphoma, brain, bone, testis, kidney---all more common in kids
D. About 5% have inherited mutations
E. Radiation is the only accepted environmental risk (ex: Chernobyl)
F. Comments:
1. Parental smoking during pregnancy—increases ALL cancers throughout life by 10%
2. Electromagnetic radiation—1 study in England found increased leukemias clustered
3. Wilms tumor—known genetic abnormalities but only 2% patients have a + family history
4. Bananas & oranges during first 2 years of life—decreases incidence of childhood leukemia
5. Hygiene Hypothesis (once again)---Acute Lymphocytic Leukemia and………..