Oncology Update

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Oncology Update
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In the beginningsperm meets the egg
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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)

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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

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Ectoderm (epithelial cells)

• the outer layer exposed to the environment
• Skin cellskeratinocytes, 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
  ectodermbut its differentmore later)

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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

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Mesoderm

• filler in the middle
• Bones
• Muscle
• Lymph tissue
• Cartilage
• Fat
• Bone marrow

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Maturation and differentiationan example in the
bone marrow (2 cell lines)
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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)

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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)

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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

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Nomenclature--is it a benign tumor?

• Add oma to the tissue type
• Glandadenoma a glandular tumor of the thyroid
  is a thyroid adenoma pituitary adenoma adenoma
  of the breast
• Boneosteoma
• Fatty tumorlipoma
• Cartilagechondroma
• Smooth muscleleiomyoma (a smooth muscle benign
  tumor of the uterus is called a leiomyoma or
  FIBROID)

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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 Cushings syndrome)

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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
• Insulinomabenign tumor of the beta cells of the
  pancreas wreaking havoc with insulin levels and
  hypoglycemia

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Other characteristics of benign tumors

• They can be removed and they dont come back
  (usually)
• They generally dont progress to a malignancy
• The cells do not shed and travel throughout the
  body to seed somewhere else (i.e., they dont
  metastasize)
• There are exceptions to all rules of course
• Neurofibromatosis (Von Recklinghausens
  disease)too many to remove and occasionally they
  will develop into a malignant tumor

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Naming malignant tumors

• Is it a carcinoma or a sarcoma?
• Carcinomas arise from ectodermal and endodermal
  derivatives
• Skin and epithelial cellslung 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)

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More nomenclature

• Bronchogenic carcinoma (lung cancer) is
  subdivided into 2 types
• Small cell carcinoma (oat cell)(Kulchitsky cell)
• Non-small cell carcinomaincludes large cell
  carcinoma, squamous cell carcinoma, and
  adenocarcinoma

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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

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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)

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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

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• 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).

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Naming malignant tumors

• Is it a sarcoma?
• Sarcomas arise from mesodermal derivatives
• Bones, muscle, cartilage, lymph tissue, bone
  marrow, fat

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Naming tumors

• Sarcomas
• Bone? Osteosarcoma
• Cartilage? Chondrosarcoma
• Fat? Liposarcoma
• Lymph? Lymphosarcoma (shortened to
  lymphomaanother misnomer as you might think it
  is a benign tumor)

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Another digression

• Lymphomas are also divided into 2 major types
• Hodgkins lymphoma (HL)
• NON-Hodgkins 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

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Mesoderm--sarcomas

• Chondrosarcoma
• (cartilage)

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• Rhabdomyosarcoma
• Rhabdo skeletal
• Myo muscle

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Nomenclatureis it a malignant tumor?

• Malignancies are also named and defined by their
  level of differentiation
• Immature, embryonicblast
• retino blast oma, glio blast oma, neuro
  blast omarapid growing tumors
• Undifferentiatedlooks embryonic and it may be
  difficult to determine where the tissue of origin
  is
• Poorly-differentiated
• Well-differentiated

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Characteristics of malignant tumors

• Malignantinvasive, 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

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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

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Grading and staging malignant tumors

• Grade I-IV or Vestablishes the aggressiveness of
  the tumor
• The lower your grade, the better
• Example Brain tumorsGrade I astrocytoma vs.
  Grade IV astrocytoma (glioblastoma multiforme)

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Grading and staging

• StagingStages I-IV establishes the amount of
  tumor in the body
• The lower your stage, the less tumor in the body
• Example Hodgkins diseaseStage I (one group of
  lymph nodes)
• Also give the stage a letterIA (without
  symptoms), IB (with symptoms)
• TNM systemtumor size, node involvement,
  metastases
• Example Breast cancer T1, N1, M0
• Tumor size, one lymph node group, no distant
  metastases
• StagingT1, N0, M0 is Stage I, Stage IIA is T0,
  N1, M0, Stage IIB is T2, N1, M0 for examples

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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
• Whos responsible for this maturation and
  differentiation of cells?

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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

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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

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Targeted therapies

• Biological response modifiers
• Monoclonal antibody that targets the HER2/neu
  proto-oncogene
• Trastuzumab (Herceptin) for breast cancer
  patients

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Oncogenes

• Oncogenes responsible for uncontrolled
  proliferation of cell growth
• Suppressor genesp53 ( 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

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Apoptosispreprogrammed 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 apoptosisbreast 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

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Tyrosine kinase

• An enzyme required for the uncontrolled growth of
  cancer cells
• Targeted therapiesa 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)

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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

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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 50s and 60s)
• Rituximab (Rituxan)targets a protein marker on B
  lymphocytesCD 20. Used to treat B-cell lymphomas
  

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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

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• Changing the hormonal milieu in prostate cancer
  patients is commonblocking testosterone,
  blocking gonadotropin releasing factor/hormone
  (Lupron)
• In the old days men with prostate cancer were
  given estrogen (DES) to change their hormonal
  environment

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• Lets change gears for a moment and talk about
  normal proliferation
• Normal growth, maturation and differentiation of
  cells

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Normal proliferationmost occurs during fetal
life as adults, cells divide as needed to
replace lost cellsepithelial 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
  controlwho gets skin cancer?
• Skin (epithelial) cellshow often?
• Sunlight and turnover
• Sunburns as a kid
• Is sunlight a double-edged sword?

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Vitamin D and other epithelial cell cancers

• Liquid sunshine

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Normal proliferation--cells lining the bronchioles

• Respiratory cellshow often?
• Cigars, cigarettes, cigarillos, pipes, passive
  smoking
• Asbestos

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Normal proliferationcells 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

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Breast ductal liningsprolonged 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?
• Womens Health Initiative
• And, now what about hormones?

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Like when you were pregnant

• Number of kids
• Kids before the age of 20

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Or breast feeding
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Age and risk for breast cancer

• 1/2044 _at_ 20
• 1/249 _at_ 30
• 1/67 _at_ 40
• 1/36_at_50
• 1/29 _at_ 60
• 1/24 _at_ 70
• 1/9 _at_ 80
• 1/8 _at_ 90

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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

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So, thenwhat 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

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Other tissues that divide constantly

• Bone marrow
• White blood cells
• Red blood cells
• Platelets
• Leukemia is a cancer of the bone marrow
• AML (t1517)
• CML (Ph chromosomet920)
• In children, the lymphocyte is the most rapidly
  dividing cellhence, ALL is most common in kids

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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 Pagets disease
• Big dogs vs. small dogs

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

• Liver undergoing active regeneration due to ETOH
  abuse
• Hepatitis B and Cactive hepatitis
• Inflammation and cancer

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Renal tubular cells

• Acute tubular necrosis (ATN) with acute renal
  failure
• Renal tubular cells have the capacity to
  regenerate

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Tissues that never have the capacity to
dividewell, almost never

• Neuronsbrain tumors involving neurons are RARE
• The majority of brain tumors involve the glial
  or supporting cells of the central nervous system
• Myocardial cellscancers of the heart muscle are
  extremely rare
• Skeletal muscle cells in teenagers and
  adultstumors are rare

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Factors that can cause a change in the growth of
tissues

• Radiation
• Sunlight
• Chemicalsasbestos, benzene, nitrosamines,
  pesticides ?
• VirusesHBV, HCV, HPV, EBV
• Bacteria (1)Helicobacter pylori
• Geneticswhos yo daddy (or momma)?

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Factors that can cause a change in the growth of
tissues

• Hormonesgrowth hormones such as insulin-like
  growth factor, growth hormone, estrogen,
  progesterone, testosterone
• Obesityincreased hormone production in fat
  tissueespecially abdominal fat tissue
• Chronic inflammationulcerative colitis, celiac
  disease, Crohns disease, rheumatoid arthritis,
  hepatitis

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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

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Growth disturbances

• Regenerationregrowth 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

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HPV and cancer

• Cervical cancer
• Cancer of the vulva
• Rectal cancer
• Penile cancer
• Oral cancer

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Growth disturbances

• Chronic inflammation and regeneration
• Helicobacter pylori
• Gastric ulcers
• Gastric carcinoma

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Growth disturbances

• hyperplasia too many cells
• Physiologic hyperplasia--breast cells at puberty
• Pathologic hyperplasia--atypical hyperplasia of
  the breast

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Growth disturbances

• Metaplasia substitution of one adult cell for
  another adult cell
• Normal cells lining the bronchiiciliated
  columnar cells with constant trauma (smoking,
  for example)the cells will change to cells
  that can take the traumasquamous cells this
  change is known as squamous metaplasia
• Barretts esophagusstomach 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!!

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

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Growth disturbances

• dysplasiaabnormal cell size and architectural
  arrangement of cells
• cervical dysplasia dysplastic nevus (mole)
• low-grade vs. high-grade dysplasia in patients
  with ulcerative colitis

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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

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CANCER PREVENTION

• Annual check-upsbreast, 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

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Mammograms every year starting at 40
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Everybody over 50--colonoscopies every 10 years
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• Yearly stool samples for occult blood

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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?

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Young guys, examine those testicles!!

• Heat and testicular cancer?
• Undescended testicles
• Plastic diapers?
• Laptops?

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Weight loss
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Abdominal obesity and cancerinflammation

• NHL -- 95
• Breast (PMF) 112
• Pancreatic -- 176
• Kidney -- 375
• Colorectal -- 46
• Ovarian -- 51
• Uterine -- 525

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Breast cancer prevention

• Failure to limit adult weight gain may account
  for one-third of all breast cancers (Thompson HJ,
  Cancer Prevention Laboratory _at_ 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

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Cancer prevention

• Does HT increase your risk of breast cancer?
• HTyes, slightly
• ET onlyno, maybe
• Fat tissue and hormones?

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Foods and cancer protection

• Indole-3 carbinolshuh? Brassica veggies
• Broccoli,
• Brussels
• sprouts
• Cabbage
• May reverse the changes observed with cervical
  dysplasia

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And dont forget your cauliflower

• Cauliflower is nothing but a cabbage with a
  college education.
• ---Mark Twain (1835-1910)

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Do forget your french friesacrylamides (?)
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Is soy protective? Depends on when you add it to
your diet

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

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Cut back on grillingif 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 1552641999)

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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.

86
Sip a bit of tea

• Green or blackbut not herbal tea.
• Polyphenolscatechins may have a couple of ways
  they protect against cancer
• Decrease the division of cells
• Increase the excretion of carcinogens
• Anti-angiogenesis
• BMJ 3181086, 1999 Nature 398381, 1999
  Medical Tribune 39913, 1998 and 4092, 1999.

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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

88
Better yet

• Combine tomatoes with broccolisynergistic action
• Eat whole foods, not supplements!
• Cook the tomatoesincrease potency
• Add a bit of olive oil

89
Eat grapes

• Loaded with ellagic acid which blocks the bodys
  production of enzymes necessary to stimulate
  cancer cell growth
• Packed with phenols and antioxidants as well
• Other foods apples, strawberries, raspberries

90
Colon cancer preventiondietary changes

• Dont 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

91
Exercise
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Stop smoking

• Chemicals and by-products of cigarette smoke
• Head and neck cancer
• Lung cancer
• Bladder cancer
• Cervical cancer in the presence of HPV

93
Vitamin D

• Get that prostate out in the sun
• But dont do it half-assed

94
Get the whole thing out in the sun where there is
plenty of vitamin D!!

• PSAa protein located on epithelial cells
  increases with increased proliferation or
  increased size of the prostate gland
• PSA velocity

95
Thank you.

• Barb Bancroft, RN, MSN, PNP
• BBancr9271_at_aol.com
• www.barbbancroft.com