Oncology Update

In the beginning…sperm meets the egg…

Sperm + egg = zygote

• 1 cell, 2 cells, 4 cells, 8, 16, 32, 64, 128

• 100 trillion cells

• Blastocyst

• 3 germ layers (first evidence of differentiation)

Differentiation

• The process of growing up• Start out as an immature, undifferentiated,

embryonic stem cell and go through various stages of differentiation to become a mature, fully differentiated adult cell

Ectoderm (epithelial cells)

• “the outer layer exposed to the environment…”• Skin cells—keratinocytes, melanocytes,

squamous cells, basal cells• Epithelial cells lining body cavities (what body

cavities?—think about it!)• Epithelial cells line the bronchioles of the lung,

the esophagus, the stomach, the GI tract, the vagina, the prostate gland, the bladder, even the ductal linings of the breast

• (The nervous system also arises from the ectoderm—but it’s different—more later)

Endoderm

• “innards”

• Glands (thyroid, anterior pituitary, pancreas, glands that produce milk in the breast, glands that produce mucous in the stomach and colon and lungs)

• The prefix for gland is “adeno”…

Mesoderm

• “filler in the middle”

• Bones

• Muscle

• Lymph tissue

• Cartilage

• Fat

• Bone marrow

Maturation and differentiation—an example in the bone marrow (2 cell lines)

Example of maturation and differentiation

• Stem cells

• Myeloblast (BM)

• Promyeloctye (BM)

• Myelocyte (BM)

• Metamyelocyte (juvenile) (BM)

• Band neutrophil (BM and PB)

• Segmented neutrophil (BM and PB)

Loss of control of normal maturation and differentiation in the bone marrow

• Leukemia (“white blood”)• Acute (total loss of control of differentiation) vs.

chronic (partial loss of control of differentiation)• Which cell line is involved? • Myeloid cell line? AML, CML • Acute myelocytic (myeloblastic) leukemia (AML),

chronic myelocytic leukemia (CML)• Lymphoid cell line? ALL, CLL• Acute lymphocytic (lymphoblastic) leukemia

(ALL), chronic lymphocytic leukemia (CLL)

Back to the basics--Neoplasms

• A neoplasm is a “new growth”

• Once this growth is removed, the pathologist determines whether it is a benign new growth or a malignant new growth

• All tumors have to have a name, so…

Nomenclature--is it a benign tumor?

• Add “oma” to the tissue type• Gland—adenoma; a glandular tumor of the

thyroid is a thyroid adenoma; pituitary adenoma; adenoma of the breast

• Bone—osteoma• Fatty tumor—lipoma• Cartilage—chondroma• Smooth muscle—leiomyoma (a smooth muscle

benign tumor of the uterus is called a leiomyoma or FIBROID)

Besides nomenclature, what makes a benign tumor “benign”?

• It grows slowly• Histologically the cells are mature and they “stick”

together• The rate of division is slow• The benign tumor cells may function as normal cells and

produce hormones from that tissue, over and above the usual output

(thyroid adenomas producing excessive thyroid hormone causing hyperthyroidism; pituitary adenomas producing excessive prolactin causing loss of libido, lactation, and amenorrhea; adrenal adenomas producing excess cortisol and causing Cushing’s syndrome)

Benign tumor of the meninges covering the brain

• Meningioma• Even tho’ tumors are histologically benign, they can

behave badly by virtue of their location (brain) causing increased intracranial pressure or by virtue of their ability to produce excess hormones

• Insulinoma—benign tumor of the beta cells of the pancreas wreaking havoc with insulin levels and hypoglycemia

Other characteristics of benign tumors

• They can be removed and they don’t come back (usually)

• They generally don’t progress to a malignancy• The cells do not “shed” and travel throughout the body to

seed somewhere else (i.e., they don’t metastasize)• There are exceptions to all rules of course• Neurofibromatosis (Von Recklinghausen’s disease)—too

many to remove and occasionally they will develop into a malignant tumor

Naming malignant tumors…

• Is it a carcinoma or a sarcoma?• Carcinomas arise from ectodermal and endodermal

derivatives• Skin and epithelial cells—lung linings (bronchogenic

carcinoma), lining of the breast ducts (ductal carcinoma) • Glands lining of the GI tract (adenocarcinoma of the

colon); glands located in the bronchioles (adenocarcinoma of the lungs)

More nomenclature

• Bronchogenic carcinoma (lung cancer) is subdivided into 2 types

• Small cell carcinoma (oat cell)(Kulchitsky cell)

• Non-small cell carcinoma—includes large cell carcinoma, squamous cell carcinoma, and adenocarcinoma

Lung cancer statistics in women

• Bigger threat than breast cancer and all other gynecological cancers combined

• 87% of lung cancers are due to smoking• Killed nearly 70,000 women in 2003• Between 1930 and 1997 the death rate from

lung cancer rose 600 percent for women, while the rate for men during that period decreased slightly

• Genetic, metabolic and hormonal factors explain the wide gap between women and men

Naming tumors…

• Type of cell can be used as a descriptor• Squamous cell carcinoma of the skin, lung,

rectum• Basal cell carcinoma of the skin• Melanocyte of the skin is a melanocarcinoma

OR melanoma (shortened version but a misnomer)

Quick digression: Characteristics of a malignant melanoma

• Asymmetrical; appearance of a new mole after 40

• Borderline irregular; bleeding• Color variation• Diameter greater than 6 mm• Elevation, erythema• Funny feeling, fast growing

• Incidence of squamous cell carcinoma and basal cell carcinoma has nearly tripled in the last 30 years among women below the age of 40

• Rate of BCC and SCC rose to 32 per 100,000 women under 40 in 2003, from 13 per 100,000 in the late 1970s

• Beach and tanning salons are the culprits• American Academy of Dermatology recently found that

only half of the 18- to 24-year olds protect themselves from the sun

• 61% of women 18 and older think they look better with a tan

• (Dr. Leslie Christenson, Mayo Clinic; JAMA September 2005).

Naming malignant tumors…

• Is it a sarcoma?

• Sarcomas arise from mesodermal derivatives

• Bones, muscle, cartilage, lymph tissue, bone marrow, fat

Naming tumors

• Sarcomas

• Bone? Osteosarcoma

• Cartilage? Chondrosarcoma

• Fat? Liposarcoma

• Lymph? Lymphosarcoma (shortened to “lymphoma”—another misnomer as you might think it is a “benign” tumor)

Another digression…

• Lymphomas are also divided into 2 major types…

• Hodgkin’s lymphoma (HL)• NON-Hodgkin’s lymphoma (NHL)• Histologic characteristics distinguish the two;

presentation is more aggressive with the NHL; age is usually young adults with HL; the very young or the very old are more likely to have NHL

Mesoderm--sarcomas

• Chondrosarcoma

• (cartilage)

• Rhabdomyosarcoma

• Rhabdo = skeletal

• Myo = muscle

Nomenclature—is it a malignant tumor?

• Malignancies are also named and defined by their level of differentiation

• Immature, embryonic=“blast”• retino “blast” oma, glio “blast” oma, neuro “blast”

oma—rapid growing tumors• Undifferentiated—looks embryonic and it may be

difficult to determine where the tissue of origin is• Poorly-differentiated• Well-differentiated

Characteristics of malignant tumors

• Malignant—invasive, lack of cohesiveness (basis for the Pap smear), proliferates rapidly

• Malignant tumors have the capacity to metastasize• 72% of lung cancers (especially small cell carcinomas)

have mets at dx; 57% of colorectal cancers; 34% of breast cancers

• The more primitive the tumor (undifferentiated, the more likely it will metastasize)—eg, oat cell, small cell of lung

Brain tumors have their own special nomenclature

• Not called carcinomas even though the nervous system is an ectodermal derivative

• Cell type + “oma”• Astrocyte + oma = astrocytoma• Glioblastoma multiforme• Medulloblastoma• Ependymal cell + oma = ependymoma• Oligodendrocyte + glioma= oligodengroglioma• Brain stem glioma

Grading and staging malignant tumors

• Grade I-IV or V—establishes the aggressiveness of the tumor

• The lower your grade, the better

• Example: Brain tumors—Grade I astrocytoma vs. Grade IV astrocytoma (glioblastoma multiforme)

Grading and staging• Staging—Stages I-IV – establishes the amount of tumor in the

body• The lower your stage, the less tumor in the body• Example: Hodgkin’s disease—Stage I (one group of lymph

nodes)• Also give the stage a letter—IA (without symptoms), IB (with

symptoms)

• TNM system—tumor size, node involvement, metastases• Example: Breast cancer T1, N1, M0 • Tumor size, one lymph node group, no distant metastases• Staging—T1, N0, M0 is Stage I, Stage IIA is T0, N1, M0, Stage

IIB is T2, N1, M0 for examples

Back to the basics of the biology of cancer…

• Biologists estimate that more than 100 million billion cells must cooperate to keep a human being healthy over the course of an 80-year lifespan

• Who’s responsible for this maturation and differentiation of cells?

Your genes…

• Highly regulated control systems located in the genetic code

• All cancer cells have serious problems with their DNA; alterations to the DNA inside cells results in cells that have “superpowers”; they can grow anywhere and can continue to divide indefinitely

• Normal human cells stop dividing after 50-70 generations

Proto-oncogenes

• Genes responsible for manufacturing proteins for normal cell growth; turned off and on when needed

• HER-2/neu is a protooncogene involved with cell growth; when this gene is amplified, cells grow much faster; present in 20-30% of primary breast cancers

• Amplification of this gene correlates with a poor prognosis in patients with breast cancer

Targeted therapies

• Biological response modifiers • Monoclonal antibody that targets the HER2/neu

proto-oncogene• Trastuzumab (Herceptin) for breast cancer

patients

Oncogenes

• Oncogenes responsible for uncontrolled proliferation of cell growth

• Suppressor genes—p53 ( a mutation or dysfunction of this suppressor gene is found in the majority of tumors);

• BRCA mutations and breast and ovarian cancers (ovarian cancer occurs in 2 in 5 women with a BRCA mutation)

• Normal risk for a lifetime for ovarian cancer without the BRCA mutation is 1 in 75

• BRCA gene and breast cancer

Apoptosis—preprogrammed cell suicide

• Programmed cell death observed in healthy cells• Cancer cells bypass this mechanism altho’ some cells of

the immune system can sometimes successfully command the cancer cell to self-destruct

• COX-2 inhibitors and apoptosis—breast and colon cancer• Vioxx (rofecoxib) was removed from the market for clotting

problems in CV patients (high doses, long-term use for greater than 18 months)

• Continues to be studied for cancer prevention• Aspirin and other COX inhibitors are also being studied• EBV produces substances that resemble Bcl-2 (a protein

that inhibits apoptosis) and subsequently block cell suicide

Tyrosine kinase

• An enzyme required for the uncontrolled growth of cancer cells

• Targeted therapies—a new class of drugs called the signal transduction inhibitors

• Inhibit the tyrosine kinase signal

• Imatinib (Gleevec)--CML

• Gefitinib (Iressa)—lung cancer (investigational for other cancers)

Epidermal growth factor receptors (EGFR); angiogenesis

• Epidermal growth factor (EGF) can fuel the fire, so to speak, as can supplying the tumors with blood vessels

• Drugs that block the receptor (EGFR) can slow down the growth of tumors

• Tarceva (erlotinib) (Lung cancer)• Cetuximab (Erbitux)—colon cancer (Martha Stewart and

ImClone)• Bevacizumab (Avastin)—inhibits angiogenesis

Targeted therapies

• Thalidomide (Thalomid) inhibits growth factors (IL-6) and angiogenesis (as exhibited in appendage growth when given during the first trimester of pregnancy in the 50’s and 60’s)

• Rituximab (Rituxan)—targets a protein marker on B lymphocytes—CD 20. Used to treat B-cell lymphomas

Targeted therapies

• Some malignant tumors, especially those that are “male only” and “female only” have receptors for their respective hormones

• Breast cancer and estrogen receptors• ER+ or ER-; If the tumor is ER+ then changing the

hormonal milieu is often very beneficial• Drugs include nolvadex (Tamoxifen), raloxifene (Evista)

—both drugs block estrogen receptors• Is there a problem with that? Tamoxifen

(agonist/antagonist)• Aromatase inhibitors--letrozole (Femara)—inhibits an

enzyme that converts estrogen to its most potent form; other aromatase inhibitors

• Changing the hormonal milieu in prostate cancer patients is common—blocking testosterone, blocking gonadotropin releasing factor/hormone (Lupron)

• In the “old days” men with prostate cancer were given estrogen (DES) to change their hormonal environment

• Let’s change gears for a moment and talk about “normal proliferation”…

• Normal growth, maturation and differentiation of cells

Normal proliferation…most occurs during fetal life; as adults, cells divide as needed to

replace lost cells—epithelial cells do the most dividing

• Dividing cells are more prone to the loss of the control of growth and DNA mutations

• The older the cells, the more prone to loss of control—who gets skin cancer?

• Skin (epithelial) cells—how often?• Sunlight and turnover• Sunburns as a kid• Is sunlight a double-edged sword?

Vitamin D and other epithelial cell cancers…

• Liquid sunshine…

Normal proliferation--cells lining the bronchioles

• Respiratory cells—how often?

• Cigars, cigarettes, cigarillos, pipes, passive smoking

• Asbestos

Normal proliferation—cells lining the gastrointestinal tract

• How often do you replace cell lining the gastrointestinal tract

• Sloughing cells and dead bacteria• Genetics and cellular turnover time• High fat diet, low fiber diet, high

nitrosamines

Breast ductal linings—prolonged hormone stimulation?

• Estrogen or progesterone?• New evidence? Maybe progesterone in PMF• LIFETIME exposure to hormones• Long period of periods• When did you start your periods, when did you

stop your periods?• Did you have a period of not having periods?• Women’s Health Initiative• And, now what about hormones?

Like when you were pregnant…

• Number of kids

• Kids before the age of 20

Or breast feeding…

Age and risk for breast cancer

• 1/2044 @ 20• 1/249 @ 30• 1/67 @ 40• 1/36@50• 1/29 @ 60• 1/24 @ 70• 1/9 @ 80• 1/8 @ 90

Prostate epithelial cells…

• The older you are, the higher the risk

• Epithelial cells and turnover

• A lifetime of testosterone

• The prostate increases in size with aging

So, then…what are the 5 most common cancers in the U.S.?

• Skin• Lung• GI• Breast• Prostate

• All of which have epithelial cells that continue to grow throughout life-- “exposed to the environment, exposed to hormones” and have the potential for growth disturbances

Other tissues that divide constantly

• Bone marrow• White blood cells• Red blood cells• Platelets• Leukemia is a cancer of the bone marrow• AML (t15:17)• CML (Ph chromosome—t9:20)• In children, the lymphocyte is the most rapidly dividing

cell—hence, ALL is most common in kids

Bone turnover

• Bone growth spurts• During the first year• And at puberty• Older adult also has more bone turnover• Highest risk for bone cancer is as an adolescent

and as an older adult• Adult with Paget’s disease• Big dogs vs. small dogs

Tissues that have the capacity to divide but only do so as necessary…

• Liver undergoing active regeneration due to ETOH abuse

• Hepatitis B and C—active hepatitis

• Inflammation and cancer

Renal tubular cells

• Acute tubular necrosis (ATN) with acute renal failure

• Renal tubular cells have the capacity to regenerate

Tissues that “never” have the capacity to divide—well, almost never…

• Neurons—brain tumors involving neurons are RARE

• The majority of brain tumors involve the “glial” or supporting cells of the central nervous system

• Myocardial cells—cancers of the heart muscle are extremely rare

• Skeletal muscle cells in teenagers and adults—tumors are rare

Factors that can cause a change in the growth of tissues…

• Radiation• Sunlight• Chemicals—asbestos, benzene, nitrosamines, pesticides

?• Viruses—HBV, HCV, HPV, EBV • Bacteria (1)—Helicobacter pylori• Genetics—who’s yo’ daddy (or momma)?

Factors that can cause a change in the growth of tissues…

• Hormones—growth hormones such as insulin-like growth factor, growth hormone, estrogen, progesterone, testosterone

• Obesity—increased hormone production in fat tissue—especially abdominal fat tissue

• Chronic inflammation—ulcerative colitis, celiac disease, Crohn’s disease, rheumatoid arthritis, hepatitis

Growth disturbances

• May be precursors to the “loss of control” and the development of cancer

• Fertile soils, so to speak• BUT, the growth disturbances are NOT

cancer, and they are reversible once the inciting stimulus is removed

• What are these growth disturbances?• Regeneration, hyperplasia, metaplasia,

dysplasia

Growth disturbances

• Regeneration—regrowth of damaged tissues (cuts, burns, the ovary following ovulation, skin damaged by sunlight, chronic liver infection with viruses, chronic alcohol and the liver)

• Chronic hepatitis C + alcohol = high risk (100 x greater) for the loss of the control of growth resulting in hepatocellular carcinoma and cirrhosis

HPV and cancer

• Cervical cancer

• Cancer of the vulva

• Rectal cancer

• Penile cancer

• Oral cancer

Growth disturbances

• Chronic inflammation and regeneration

• Helicobacter pylori

• Gastric ulcers

• Gastric carcinoma

Growth disturbances

• hyperplasia – too many cells

• Physiologic hyperplasia--breast cells at puberty• Pathologic hyperplasia--atypical hyperplasia of

the breast

Growth disturbances

• Metaplasia – substitution of one adult cell for another adult cell

• Normal cells lining the bronchii—ciliated columnar cells; with constant trauma (smoking, for example)—the cells will “change” to cells that can take the trauma—squamous cells; this change is known as squamous metaplasia

• Barrett’s esophagus—stomach cells lining the esophagus (columnar epithelial cells)(normal lining of the esophagus is squamous epithelium)

• Acid reflux and irritation of the lower esophagus might play a BIG role

• Take those PPIs!!

• Metaplasia (the substitution of one adult cell for another adult cell usually as an adaptive substitution)—intestinal metaplasia and Barrett’s esophagus (intestinal metaplasia vs. the normal stratified squamous cells of the lower 1/3 of the esophagus)

Growth disturbances

• dysplasia—abnormal cell size and architectural arrangement of cells

• cervical dysplasia; dysplastic nevus (mole)

• low-grade vs. high-grade dysplasia in patients with ulcerative colitis

Growth disturbances

• All of the aforementioned growth disturbances are considered “reversible”

• If the inciting stimulus is removed• How long do the changes take?• An example of cervical cancer• Changes may take 16-25 years• Human papilloma virus initiates the changes• Co-infected with HIV or HSV? – promotes the

changes

CANCER PREVENTION

• Annual check-ups—breast, prostate, skin• Colonoscopies every 10 years• Pap smears• HPV vaccine is now available!! YES! When

should it be given?• Eat right• Exercise• Stop smoking• Lose weight

Mammograms every year starting at 40**

Everybody over 50--colonoscopies every 10 years

• Yearly stool samples for occult blood

Guys, get those prostates checked! (starting at age 40)

• Comments from patients during rectal exams: (Dr. James Ralph)

• “Find Amelia Earhart yet?”• “Can you hear me NOW?”• “Hey, now I know how a muppet feels…”• “How long have you been in politics?”• “Remind me never to become an altar boy.”• “Could you write me a note for my wife, saying that my

head is not, in fact, up there?”

Young guys, examine those testicles!!

• Heat and testicular cancer?

• Undescended testicles

• Plastic diapers?

• Laptops?

Weight loss…

Abdominal obesity and cancer…inflammation

• NHL -- +95%

• Breast (PMF) – 112%

• Pancreatic -- +176%

• Kidney -- +375%

• Colorectal -- +46%

• Ovarian -- +51%

• Uterine -- +525%

Breast cancer prevention

• Failure to limit adult weight gain may account for one-third of all breast cancers (Thompson HJ, Cancer Prevention Laboratory @ Colorado State University, Fort Collins, CO)

• Weight gain of more than 11 pounds as an adult, along with less than 30 minutes of physical activity daily, is linked to an increased risk of breast cancer

Cancer prevention

• Does HT increase your risk of breast cancer?

• HT—yes, slightly

• ET only—no, maybe

• Fat tissue and hormones?

Foods and cancer protection

• Indole-3 carbinols—huh? Brassica veggies• Broccoli, • Brussels

sprouts• Cabbage• May reverse the changes observed with cervical

dysplasia

And don’t forget your cauliflower…

• “Cauliflower is nothing but a cabbage with a college education.”

---Mark Twain (1835-1910)

Do forget your french fries…acrylamides (?)

Is soy protective? Depends on when you add it to your diet…

• Add 25 gm of soy products per day—soy beans, soy milk, soy burgers, soy sauce (not!) at puberty NOT at menopause

Cut back on grilling…if you have to grill, marinate the meat (in a sweetened oil and vinegar sauce overnight to

reduce HCA formation)

• Most of the HCAs are found in the crisp black outer crust of the steak or meat that has been grilled, so the more the meat is well done, the higher the risk.

• Microwave to precook it before grilling. Microwaving evaporates much of the water, zapping the HCAs in the process

• Flip the burgers constantly • Add fruit to the meat before it is grilled, such as

ground tart cherries, and reduce the HCA content by up to 90%.

• (Science News 155;264:1999)

Cut back on the booze…

• Folic acid supplements• Alcohol is on the list of “probable cause” for

cancers of the colon, rectum and breast; “convincing cause” of cancers of the mouth and pharynx, larynx, esophagus, liver, and “possible cause” for lung cancer.

Sip a bit of tea…

• Green or black—but not herbal tea.• Polyphenols—catechins may have a couple of ways they

protect against cancer• Decrease the division of cells• Increase the excretion of carcinogens• Anti-angiogenesis • BMJ 318:1086, 1999; Nature 398:381, 1999; Medical

Tribune 39#9:13, 1998 and 40#9:2, 1999.

Coffee enemas

• With the re-emergence of complementary and alternative therapies, daily coffee enemas have re-emerged as detoxifying agents in an alternative cancer therapy program known as the Gonzalez/Kelley treatment regimen for pancreatic cancer.. The mechanism of action --smooth muscle relaxation of the hepatic ducts resulting in increased secretion of toxins from the liver into the GI tract and out of the body.

• Rectal administration only

Better yet…

• Combine tomatoes with broccoli—synergistic action

• Eat whole foods, not supplements!

• Cook the tomatoes—increase potency

• Add a bit of olive oil…

Eat grapes…

• Loaded with ellagic acid which blocks the body’s production of enzymes necessary to stimulate cancer cell growth

• Packed with phenols and antioxidants as well• Other foods: apples, strawberries, raspberries

Colon cancer prevention—dietary changes

• Don’t forget fiber• Vitamin D detoxifies our digestive juices• Increased folic acid converts homocysteine to

methionine which protects DNA from damage• Calcium also plays a role in colon cancer

prevention

Exercise

Stop smoking

• Chemicals and by-products of cigarette smoke

• Head and neck cancer

• Lung cancer

• Bladder cancer

• Cervical cancer in the presence of HPV

Vitamin D

• Get that prostate out in the sun

• But don’t do it half-assed…

Get the whole thing out in the sun where there is plenty of vitamin D!!

• PSA—a protein located on epithelial cells; increases with increased proliferation or increased size of the prostate gland

• PSA velocity

Thank you.

• Barb Bancroft, RN, MSN, PNP

• BBancr9271@aol.com• www.barbbancroft.com