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The Nature of Disease
Pathology for the Health Professions
Thomas H. McConnell
Chapter 5
Neoplasia
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Overview of Today’s Lecture
• Today’s Lecture
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Characteristics and Definition of Cancer
General causes of cancer
Molecular Basis of Cancer
Biology of Neoplastic Growth
Clinical Manifestations
Treatment
Early Detection and Prevention
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Cancer
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Derived from Greek word for crab, karkinoma
Malignant tumor – cancerous growth
Tumor – a new growth (not necessarily cancerous)
Incidence dependent on many factors
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Age
Genetics
Gender
See this link from NCI’s SEER Report
Ethnicity
Life-style
Infection
Inflammation
• Oncology is the study of cancer
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Incidence of Cancer Cases and Deaths in US
Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
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Some Definitions
• Neoplasm – any abnormal growth of new cells
• Tumors are neoplasms and can be divided into:
– Benign – usually no capacity to spread from site of
origin
– Malignant
• Has the capacity to spread and cause death
• Also known as a cancer
• Oncology is the study of neoplasms
• Carcinoma in situ – Neoplasia confined to an
epithelium; has not penetrated basement
membrane
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Hallmarks of Neoplasms
• The biologic capabilities of neoplasms are
characteristic:
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Self-sufficiency of growth (“go”) signals
Evasion of growth suppression (“stop”) signals
Capability to divide indefintely
Escape apoptosis (PCD)
Recruit new blood vessels (angiogenesis)
If malignant, invasion of nearby tissue and distant
spread
– Evade immune surveillance
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Hallmarks of Cancer
Key Pathways
Supporting Pathways
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Nomenclature (Naming) of Tumors
Connective
tissue and
Muscle
& Cardiac
Epithelial
tissue
Blood cells
Table from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
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Causes of Cancer
List…
** The caused of all
cancer is damaged
(mutated) DNA
Ex:
Heterocyclic
amines
(HAC),
polyaromatic
hydrocarbons
(PAH)
Some cancers have a
genetic predisposition
due to inherited
mutations in germ
cells, ova and sperm.
Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
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Molecular Basis of Neoplasia
•The cause of all cancer is DNA mutation.
– Proto-oncogenes (“go”)
– Tumor supressor genes (“stop”)
– Apoptosis regulator genes (e.g., p53)
– DNA repair genes
• Carcinogenesis is a multistep process.
• Most cancer-related mutations occur in somatic cells
• Inheritable cancer syndromes (about 20) result from
mutations in germ cells
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Cancer-Causing Mutations
• Cancer is generally considered
– a disease of aging
– a disease of DNA
• Multiple genetic mutations are
required before cancer can develop
• Clonal proliferation or expansion
– As a result of a mutation, a cell acquires
characteristics that allow it to have
selective advantage over its neighbors
• Increased growth rate or decreased apoptosis
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Inflammation and Cancer
• Chronic inflammation may be an important
factor in the development of cancer
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Cytokine release from inflammatory cells
Free radicals
Mutation promotion
Decreased response to DNA damage
Examples: ulcerative colitis, chronic viral hepatitis,
Barrett’s esophagus
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Clonal Proliferation of Cancer Cells
Notice that the population of cells above contains cells that
are genetically and morphologically distinct - heterogeneity
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Guardians of the Genome DNA Repair Genes
• Integrity of DNA can be compromised at several key
points
– DNA synthesis
– Sister chromatid segregation
– Mutation by external mutagens
• Caretaker genes (Mutator genes, DNA Repair)
– Direct synthesis of proteins involved in maintaining integrity
of the genome
– Encode for proteins that are involved in repairing damaged
DNA, e.g., BRCA-1/2
– Some inherited mutations in caretaker genes
• Xeroderma pigmentosum (XP)
• Hereditary nonpolyposis colorectal cancer (HNPCC)
• Whole genome threats: Bloom syndrome, Fanconi anemia
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Genetics and Cancer-Prone Families
• Mutagen exposure and mutation
– Somatic cells mutations are not transferred to offspring
– Germ cell mutations can be transferred
• Usually in tumor suppressor gene
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Retinoblastoma (RB gene)
Wilms’ tumor (WT1 gene)
Neurofibromatosis (NF1 gene)
Breast cancer (BRCA1 gene)
Polyposis coli/colon cancer (APC gene)
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Molecular Basis of Neoplasia
• Proto-oncogenes
– Normal (non-mutated) genes that direct/stimulate
protein synthesis and cellular growth
• Oncogenes
– Mutant genes that escape normal regulatory controls
• Tumor-suppressor genes
– Encode proteins that in their normal state negatively
regulate, i.e., suppress proliferation
– Mutation/inactivation allows uncontrolled growth
– Also referred to as anti-oncogenes
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Cancer Caused by Oncogenes
Figure from: Alberts et al., Essential Cell Biology, Garland Press, 1998
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Proto-oncogenes
RAS = Rat Sarcoma
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Biology of Neoplastic Growth
Cells proceed through premalignant changes
after DNA damage
- Metaplasia (reversible)
- Dysplasia (precancerous, may be
reversible)
Figure from:
McConnell,
The Nature of
Disease, 2nd
ed., Wolters
Kluwer, 2014
- Carcinoma in situ
- Local invasion (hallmark of cancer)
- Metastasis (discontinuous, distant spread)
- Hematogenous
- Lymphatic spread
- Seeding (local spread in fluids)
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Angiogenesis
• Growth of new vessels
• Advanced cancers can
secrete angiogenic
factors (VEGF)
– Vascular endothelial GF
– Platelet derived GF
– Basic fibroblast GF
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Immune System and Cancer
• Normal immune system protects against cancer –
Immune Surveillance
• Immunosuppression increases likelihood of
cancer
– Non-Hodgkin lymphoma (10X)
– Kaposi sarcoma (1000X)
• In some cases, cancer promotes secretion of
cytokines that promote growth of cancer
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Cancer Progression
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Tumor Growth Rate Depends on Growth Fraction
Tumor doubling time
How Growth Fraction Affects Tumor Growth Rate – the
fraction of cells that are dividing
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Figures from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
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Loss of Differentiation in Cancer Development
Colon epithelium and
development of cancer
Anaplasia = reversion
of differentiation to an
earlier state, i.e., loss
of differentiation.
A hallmark of cancer.
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Clinical Manifestations of Neoplasia
• Symptoms arise from:
– Pressure on local tissues/structures
– Ulceration with bleeding and/or
infection
– Infarction or rupture
– Generalized wasting (cachexia)
– Production of hormones or other
molecules that affect distant organs
• Paraneoplastic syndrome – distant effects NOT due to
local invasion or metastasis
• A good clinical history is critical to diagnosis
and treatment
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Clinical Manifestations of Cancer
• Paraneoplastic syndromes
– Symptom complexes not caused by direct local effects of cancer
– Caused by biologic substances released from cancer or immune responses to
cancer
– Examples:
• Release of serotonin and other hormones by carcinoid (neuroendocrine) tumors
– Flushing, diarrhea, wheezing, rapid heartbeat
• Antibody response to tumor that results in attack on the nervous system
• Wide variety of symptoms and signs associated with cancer
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Pain
Fatigue
Cachexia
Anemia
Leukopenia and thrombocytopenia
GI symptoms
Integumentary manifestations
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Clinical Manifestations of Cancer - Pain
• Pain
– Most commonly, little or no pain is associated with early
stages of many malignancies
– Influenced by fear, anxiety, sleep loss, fatigue, and overall
physical deterioration
– Mechanisms causing pain:
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Pressure
Obstruction
Invasion of sensitive structures
Stretching of visceral surfaces
Tissue destruction
Inflammation
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Clinical Manifestations of Cancer - Fatigue
• Fatigue
– Subjective clinical manifestation
– Tiredness, weakness, lack of energy, exhaustion, lethargy,
inability to concentrate, depression, sleepiness, boredom,
and lack of motivation
– Possible causes:
• Sleep disturbance
• Biochemical changes from circulating cytokines secondary to
disease and treatment
• Psychosocial factors
• Level of activity
• Nutritional status
• Environmental factors
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Clinical Manifestations of Cancer - Cachexia
• Syndrome of cachexia
– Most severe form of
malnutrition
– Present in 80% of cancer
patients at death
– Includes anorexia, early
satiety, weight loss,
anemia, asthenia, taste
alterations, and altered
protein, lipid, and
carbohydrate metabolism
Figure from: Huether & McCance, Understanding
Pathophysiology, 5th ed., Elsevier, 2012
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Hematologic Clinical Manifestations of Cancer
• Anemia
– A decrease of hemoglobin in the blood
– Mechanisms:
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Chronic bleeding resulting in iron deficiency
Severe malnutrition
Medical therapies
Malignancy in blood-forming organs
• Leukopenia and thrombocytopenia
– Direct tumor invasion to the bone marrow causes leukopenia
and thrombocytopenia
– Chemotherapy drugs are toxic to the bone marrow
• Infection
– Risk increases when the absolute neutrophil and lymphocyte
counts fall
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Clinical and Laboratory Assessment of Neoplasms
• Generally, clinically discernible masses require biopsy
and microscopic study (unless type is apparent)
– Cytology, e.g, Pap smear
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Biopsy
Fine needle aspiration (may eliminate need for biopsy)
Flow cytometry
Immunohistochemistry
Tumor markers
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Tumor Markers
• Tumor cell markers (biologic markers)
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substances produced by both benign and malignant cells
found in cells or on plasma cell membranes, in the blood, CSF, or urine
Gene transcription products
Hormones, Enzymes, Antigens, Antibodies
Examples:
• alpha fetoprotein (AFP; germ cells)
• prostate specific antigen (PSA; prostate cells)
• Tumor markers are used to:
– Screen and identify individuals at high risk for cancer – but not good for
early detection
– Diagnose specific types of tumors (and arrive at individualized treatment
options)
– Observe clinical course of cancer
• Problem: false positives and false negatives
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Tumor Markers – Aids to Classification and Treatment
See this LINK for more information about breast cancer subtypes.
Figure from: Huether & McCance, Understanding Pathophysiology, 5th ed., Elsevier, 2012
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Neoplasms Vary in Anatomy and Behavior
Table from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
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Gross Structure of Neoplasms
Image from: http://www.imagekb.com/colon-polyps
Intestinal polyp
Benign vs. Malignant neoplasms
Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
Image from: http://www.papilloma-virus.com/oralpapilloma-pictures_18.html
Oral papilloma
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Cancer Staging
• Microscopic analysis for staging-based
presence of metastasis
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Stage I: No metastasis
Stage II: Local invasion
Stage III: Spread to regional structures
Stage IV: Distant metastasis
• World Health Organization’s TNM system:
– T for tumor spread
– N for node involvement
– M for the presence of distant metastasis
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TNM Cancer Grading System
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Overview of Cancer Treatments
Table from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014
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Cancer Treatment – Surgery; Hormone Therapy
• Surgery
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To prevent cancer (colon polyps)
Biopsy for diagnosis and staging
Lymph node sampling - Sentinel nodes
De-bulking surgery
Palliative surgery
Sometimes destruction without removal is desired
• Radiofrequency (RF) ablation
• Cryotherapy
• Laser therapy
• Hormone therapy
– Receptor activation or blockage
– Interferes with cellular growth and signaling
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Cancer Treatment – Radiation
• Ionizing radiation
– Goals
• Eradicate cancer without excessive toxicity
• Can avoid damage to normal structures better than chemotherapy
– Ionizing radiation damages the cancer cell’s DNA
– May be external, internal, or systemic
Stereotactic body radiation therapy
(SBRT) delivers very targeted beams
of radiation to a small area over a
few days and is less invasive than
surgery. Researchers demonstrated
that SBRT for early stage, medically
inoperable non-small cell lung
cancer doubled overall survival rates
compared with conventional
radiation. Image courtesy of Yasushi
Nagata, M.D.
From: https://www.rsna.org/NewsDetail.aspx?id=9297
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Cancer Treatment - Chemotherapy
• Chemotherapy (Induction, Adjuvant, Neoadjuvant)
– Use of nonselective cytotoxic drugs
• target vital cellular machinery
• metabolic pathways critical, but common, to both malignant and
normal cell growth and replication
– Goal
• Eliminate enough tumor cells so the body’s defense can eradicate
any remaining cells
• The most hardy cells and resistant cells may be the ones that are able
to metastasize
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Single-agent chemotherapy
Combination chemotherapy
Principle of dose intensity
Administration schedule very important
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Early Detection and Prevention
Last Medical Review: 03/11/2015
Last Revised: 03/11/2015
From: http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/americancancer-society-guidelines-for-the-early-detection-of-cancer
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Early Detection and Prevention
Last Medical Review: 03/11/2015
Last Revised: 03/11/2015
From: http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/americancancer-society-guidelines-for-the-early-detection-of-cancer
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Early Detection and Prevention
Last Medical Review: 03/11/2015
Last Revised: 03/11/2015
From: http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/americancancer-society-guidelines-for-the-early-detection-of-cancer
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Early Detection and Prevention
**Remember: regular
colonoscopy reduces the
death rate from colorectal
cancer by more than 50%
From:
http://www.cancer.org/healthy/findcancere
arly/cancerscreeningguidelines/americancancer-society-guidelines-for-the-earlydetection-of-cancer
Last Medical Review: 03/11/2015
Last Revised: 03/11/2015
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