Neoplasia

1
The Nature of DiseasePathology for the Health
Professions Thomas H. McConnell

• Chapter 5
• Neoplasia

2
Overview of Todays Lecture

• Todays Lecture
• Characteristics and Definition of Cancer
• General causes of cancer
• Molecular Basis of Cancer
• Biology of Neoplastic Growth
• Clinical Manifestations
• Treatment
• Early Detection and Prevention

3
Cancer

• Derived from Greek word for crab, karkinoma
• Malignant tumor cancerous growth
• Tumor a new growth (not necessarily cancerous)
• Incidence dependent on many factors
• Age
• Genetics
• Gender
• Ethnicity
• Life-style
• Infection
• Inflammation
• Oncology is the study of cancer

See this link from NCIs SEER Report
4
Incidence of Cancer Cases and Deaths in US
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
5
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

6
Hallmarks of Neoplasms

• The biologic capabilities of neoplasms are
  characteristic
• 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

7
Hallmarks of Cancer
Key Pathways
Supporting Pathways
Figure from Huether McCance, Understanding
Pathophysiology, 5th ed., Elsevier, 2012
8
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
9
Causes of Cancer
List
The caused of all cancer is damaged (mutated)
DNA Some cancers have a genetic predisposition
due to inherited mutations in germ cells, ova and
sperm.
Ex Heterocyclic amines (HAC), polyaromatic
hydrocarbons (PAH)
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
10
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

12
Inflammation and Cancer

• Chronic inflammation may be an important factor
  in the development of cancer
• Cytokine release from inflammatory cells
• Free radicals
• Mutation promotion
• Decreased response to DNA damage
• Examples ulcerative colitis, chronic viral
  hepatitis, Barretts esophagus

13
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
14
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

15
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
• Retinoblastoma (RB gene)
• Wilms tumor (WT1 gene)
• Neurofibromatosis (NF1 gene)
• Breast cancer (BRCA1 gene)
• Polyposis coli/colon cancer (APC gene)

16
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

17
Cancer Caused by Oncogenes
Figure from Alberts et al., Essential Cell
Biology, Garland Press, 1998
18
Proto-oncogenes
RAS Rat Sarcoma
Figure from Huether McCance, Understanding
Pathophysiology, 5th ed., Elsevier, 2012
19
Biology of Neoplastic Growth

• Cells proceed through premalignant changes after
  DNA damage
• Metaplasia (reversible)
• Dysplasia (precancerous, may be reversible)
• Carcinoma in situ
• Local invasion (hallmark of cancer)
• Metastasis (discontinuous, distant spread)
• Hematogenous
• Lymphatic spread
• Seeding (local spread in fluids)

Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
20
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
21
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

22
Cancer Progression
Figure from Huether McCance, Understanding
Pathophysiology, 5th ed., Elsevier, 2012
23
Tumor Growth Rate Depends on Growth Fraction
Tumor doubling time
How Growth Fraction Affects Tumor Growth Rate
the fraction of cells that are dividing
2
30
40
Figures from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
24
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
25
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

26
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
• Pain
• Fatigue
• Cachexia
• Anemia
• Leukopenia and thrombocytopenia
• GI symptoms
• Integumentary manifestations

27
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
• Pressure
• Obstruction
• Invasion of sensitive structures
• Stretching of visceral surfaces
• Tissue destruction
• Inflammation

28
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

29
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
30
Hematologic Clinical Manifestations of Cancer

• Anemia
• A decrease of hemoglobin in the blood
• Mechanisms
• 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

31
Clinical and Laboratory Assessment of Neoplasms

• Generally, clinically discernible masses require
  biopsy and microscopic study (unless type is
  apparent)
• Cytology, e.g, Pap smear
• Biopsy
• Fine needle aspiration (may eliminate need for
  biopsy)
• Flow cytometry
• Immunohistochemistry
• Tumor markers

32
Tumor Markers

• Tumor cell markers (biologic markers)
• 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

33
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
34
Neoplasms Vary in Anatomy and Behavior
Table from McConnell, The Nature of Disease, 2nd
ed., Wolters Kluwer, 2014
35
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/oral-pa
pilloma-pictures_18.html
Oral papilloma
36
Cancer Staging

• Microscopic analysis for staging-based presence
  of metastasis
• Stage I No metastasis
• Stage II Local invasion
• Stage III Spread to regional structures
• Stage IV Distant metastasis
• World Health Organizations TNM system
• T for tumor spread
• N for node involvement
• M for the presence of distant metastasis

37
TNM Cancer Grading System
38
Overview of Cancer Treatments
Table from McConnell, The Nature of Disease, 2nd
ed., Wolters Kluwer, 2014
39
Cancer Treatment Surgery Hormone Therapy

• Surgery
• 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

40
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 cells 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?id9297
41
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 bodys
  defense can eradicate any remaining cells
• The most hardy cells and resistant cells may be
  the ones that are able to metastasize
• Single-agent chemotherapy
• Combination chemotherapy
• Principle of dose intensity
• Administration schedule very important

42
Early Detection and Prevention
Last Medical Review 03/11/2015Last Revised
03/11/2015
From http//www.cancer.org/healthy/findcancerearl
y/cancerscreeningguidelines/american-cancer-societ
y-guidelines-for-the-early-detection-of-cancer
43
Early Detection and Prevention
Last Medical Review 03/11/2015Last Revised
03/11/2015
From http//www.cancer.org/healthy/findcancerearl
y/cancerscreeningguidelines/american-cancer-societ
y-guidelines-for-the-early-detection-of-cancer
44
Early Detection and Prevention
Last Medical Review 03/11/2015Last Revised
03/11/2015
From http//www.cancer.org/healthy/findcancerearl
y/cancerscreeningguidelines/american-cancer-societ
y-guidelines-for-the-early-detection-of-cancer
45
Early Detection and Prevention
Remember regular colonoscopy reduces the death
rate from colorectal cancer by more than 50
From http//www.cancer.org/healthy/findcancerearl
y/cancerscreeningguidelines/american-cancer-societ
y-guidelines-for-the-early-detection-of-cancer
Last Medical Review 03/11/2015Last Revised
03/11/2015