ONCOLOGY

GERARD FRANCIS M. LUDOVICE

D E PA RT M E N T O F S U R G E RY
BICOL MEDICAL CENTER
Introduction
Modern cancer therapy is multidisciplinary, involving coordinated care by
surgeons, medical oncologists, radiation oncologists, reconstructive surgeons,
pathologists, radiologists, and primary care physicians.
Understanding cancer biology is essential to successfully implement
personalized cancer therapy
The following alterations are critical for malignant cancer growth: self-sufficiency
of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis,
potential for limitless replication, angiogenesis, invasion and metastasis,
reprogramming of energy metabolism, and evading immune destruction
Neoplasm
Altered cell population characterized by an excessive, non useful proliferation of cells
that are unresponsive to normal control mechanisms and to organizing influences of
adjacent tissue.
Benign:
◦ Composed of normal appearing cells that do not invade locally or metastasize to
other sites
Malignant:
◦ Cancer cells that exhibit uncontrolled proliferation and impair the function of normal
organs by local tissue invasion and metastatic spread to distant anatomic sites.
EPIDEMIOLOGY
Overall cancer death rates shows slow steady increase
Increase death rates:
◦ Lung
◦ Pancreas
Lower death rates during past 50 years:
◦ Stomach
◦ Uterus
USA
USA
In the Philippines
The most significant 5 year survival rates are achieved in patients with cancer of:
◦ Skin
◦ Thyroid
◦ Cervix
◦ Uterus
◦ Bladder

Lowest survival with pancreatic cancer

ETIOLOGY
1. Chemical Carcinogens
◦ Hydrocarbons from coal tar = skin, larynx and bronchial CA
◦ Aromatic amines = urinary tract CA
◦ Benzene = leukemia
◦ Asbestos = mesothelioma
2. Physical Carcinogens
◦ Ionizing radiations = bone cancer
◦ Multiple x-rays = skin/thyroid cancer
◦ Atomic bomb (Japan) = leukemia
3. Mechanical (chronic irritation)
◦ Marjolin’s ulcer = burn scar cancer
4. Infection
◦ Viruses
◦ Hepatitis B – Hepatocellular CA
◦ Epstein Barr virus – Burkitts lymphoma
◦ Herpes simplex virus 2 – cervical CA
◦ Aids
◦ Parasitic
◦ Schistosomas –liver and bladder CA
Precancerous conditions
Leucoplakia
Actinic Keratosis
Polyps of colon and rectum
Neurofibromas
Dysplasia of cervix, bronchial
Chronic ulcerative colitis
Hereditary factors
Familial polyposis – Colonic Ca
Breast Ca – 2-3x in daughters and in younger age
Oncogenes and Growth factors
RNA tumor viruses cause:
1. Carcinomas
2. Sarcoma
3. Leukemia
4. Lymphomas
Retrovirus have an enzyme that alters genomic RNA resulting to abnormal growth and
differentiation of the cell
Multifactorial:
Lung and Breast
BIOLOGY
6 essential alterations in cell physiology:
◦ Self-sufficiency of growth signals
◦ Insensitivity to growth-inhibitory signals
◦ Evasion of apoptosis (programmed cell—reprogramming of energy metabolism and
evading immune destruction death)
◦ Potential for limitless replication
◦ Angiogenesis
◦ Invasion and metastasis.
BIOLOGY
Morphologic Changes:
◦ Rise from a single cell
◦ Revert to a more primitive cell types
◦ Normal orderly tissue patterns are lost or replaced by random pilling up of malignant
cells w/o definitive pattern
◦ High index of mitoses
◦ Invasion of adjacent structures
Cancer Initiation
Tumorigenesis: 3 steps: Initiation; promotion and progression;
Initiating: events such as gain of function of genes known as oncogenes or loss of
function of genes known as tumor-suppressor genes may lead a single cell to acquire a
distinct growth advantage.
Mutations in at least four or five genes are required for formation of a malignant tumor,
while fewer changes suffice for a benign tumor
Gene expression is a multistep process that starts from transcription of a gene into
messenger ribonucleic acid (mRNA) and then translation of this sequence into the
functional protein.
Alterations at the genome level (e.g., amplifications of a gene)
Alterations at the transcription level (e.g., methylation of the DNA leading to
transcriptional silencing)
level of mRNA processing, mRNA stability, mRNA translation, or protein stability
all can alter the levels of critical proteins and thus contribute to tumorigenesis.
Cell cycle dysregulation in Cancer
Divided in to four phases:
◦ Synthetic or S phase:
◦ cell generates a single copy of its genetic material
◦ Mitotic or M phase:
◦ cellular components (including copies of DNA) are partitioned between two
daughter cells
◦ G1 and G2 (Gap phases)
◦ cells prepare themselves for completion of the S and M phases, respectively
◦ G0 or Quiescent state:
◦ cease proliferation, exit the cell cycle.
2 Regulatory molecules
Cyclins
◦ Cyclins serve a regulatory function and are synthesized at specific times during the
cell cycle.
Cyclin-dependent kinases (CDKs), which associate to form an activated heterodimer.
◦ Catalytic activity (phosphorylation of downstream proteins)

(CDK interacting protein/Kinase inhibitory protein) family and the INK4a/ ARF (Inhibitor
of Kinase 4/Alternative Reading Frame) family
◦ prevent the progression of the cell cycle.
◦ Mutation or altered expression of these genes can lead to tumor formation.
Biochemical changes:
Changes in DNA, RNA and loss of CONTACT INHIBITION to proliferation and intercellular
adhesiveness
Reversion of normal cellular biochemistry to that of the embryonal cells that produces
EMBRYONAL subs. (CEA, Alpha fetoprotein)
Growth rates of neoplasm:
◦ Doubling time is doubled
◦ Takes 30 doubling time to produce a 1cm nodule
Effector mechanism in tumor immunity
Host provides a number of effector mechanism that destroys the tumor:
1. Tumor – antigen – specific antibodies
2. Mononuclear phagocytes
3. Natural killer cells
4. Cytotoxic T lymphocytes
5. Neutrophils
6. K cells
Tumor Necrosis Factor (TNF)

Cytokines produced by monocytes, macrophages, endothelial cells, large granular

lymphocytes and neutrophils

Properties:
◦ Direct cytotoxicity for certain cells
◦ Stimulation of procoagulant activity by vascular endothelial cells
◦ Induction of fever by direct effect on the hypothalamic thermoregulatory center
Oncogenes
Normal cellular genes that contribute to cancer when abnormal are called oncogenes.
Counterpart proto-oncogenes.
Growth factors (e.g., platelet-derived growth factor)
Growth factor receptors (e.g., HER2)
Intracellular signal transduction molecules (e.g., ras)
Nuclear transcription factors (e.g., c-myc)
other molecules involved in the regulation of cell growth and proliferation
Alterations in Apoptosis
Mitochondrial pathway
(Intrinsic) pathway, death results from the release of cytochrome c from the mitochondria.
Cytochrome c, procaspase 9, and apoptotic protease activating factor 1 (Apaf-1) form an enzyme
complex, referred to as the apoptosome, that activates the effector caspases.
Stimulated by DNA damage, reactive oxygen species, or the withdrawal of survival factors.

Death receptor pathway

(extrinsic) pathway. Cell-surface death receptors include Fas/APO1/CD95, tumor necrosis factor
receptor 1, and KILL-ER/DR5, which bind their ligands Fas-L, tumor necrosis factor (TNF), and TNF-
related apoptosis-inducing ligand (TRAIL), respectively. When the receptors are bound by their ligands,
they form a death-inducing signaling complex (DISC). At the DISC, procaspase 8 and procaspase 10 are
cleaved, yielding active initiator caspases
Aberrations in the apoptotic program
Increased expression of Fas and TRAIL decoy receptors
Increased expression of antiapoptotic Bcl-2
Increased expression of the IAP-related protein surviving
Increased expression of c-FLIP
Mutations or downregulation of proapoptotic Bax, caspase 8, APAF1, XAF1, and death
receptors CD95, TRAIL-R1, and TRAIL-R2
Alterations of the p53 pathway
Overexpression of growth factors and growth factor receptors
Activation of the PI3K/Akt survival pathway.
Autophagy
Mechanism for the delivery of cellular materials to lysosomes for degradation
Leads to the basal turnover of cell components and provides energy and
macromolecular precursors
Maintain a balance between anabolism and catabolism for normal cell growth and
development
Plays an essential role during starvation, cellular differentiation, cell death, and aging.
Involved in the elimination of cancer cells by triggering a nonapoptotic cell death
program,
Cancer Invasion
Tumors in which the malignant cells appear to lie exclusively above the basement
membrane are referred to as in situ cancer.
Carcinoma in situ has cytologic characteristic of malignant tumors but with no
detectable invasion into the surrounding tissue or infiltration into deeper cell layers.
Tumors in which the malignant cells are demonstrated to breach the basement
membrane, penetrating into surrounding stroma, are termed invasive cancer.
Ability to invade involves changes in adhesion, initiation of motility, and proteolysis of
the extracellular matrix (ECM).
Angiogenesis
Establishment of new blood vessels from a preexisting vascular bed
Neovascularization is essential for tumor growth and metastasis.
Tumors develop an angiogenic phenotype as a result of accumulated genetic alterations
and in response to local selection pressures such as hypoxia.
Many of the common oncogenes and tumor-suppressor genes have been shown to play
a role in the induction of angiogenesis
Metastasis
spread of cancer cells from the primary site and the formation of new tumors in distant
sites.
Consists of a series of steps:
1. Must develop access to the circulation through either the blood circulatory system or
the lymphatic system.
2. Circulating cells lodge in a new organ and extravasate into the new tissue.
3. Initiate growth in the new tissue and eventually establish vascularization to sustain
the new tumor.
Pathology
Classification of Neoplasm

1. Carcinoma – arising from endothelial cells

2. Sarcoma – arise from connective tissue and cells of mesenchymal origin (fibrous,
muscular, fatty, vascular and skeletal)
Grading malignancy
Broders Classification:
1. Degree of differentiation
2. Appearance of cells, their nuclei and number of mitotic figures
Grade I – least malignant
Grade IV – most malignant
Routes of Spread
Direct extension
Lymphatic spread
◦ Common in epithelial neoplasms of all types (except for basal cell CA)
Vascular spread
◦ Common in sarcomas
Spread through serous cavities
◦ Peritoneal seedings (gastrointestinal CA)
Genes Associated With Hereditary
Cancer Risk
Factors may suggest the presence of a hereditary cancer:
1. Tumor development at a much younger age than usual
2. Presence of bilateral disease
3. Presence of multiple primary malignancies
4. Presentation of a cancer in the less affected sex (e.g., male breast cancer)
5. Clustering of the same cancer type in relatives
6. Occurrence of cancer in association with other conditions such as mental retardation
or pathognomonic skin lesions
CARCINOGENS
Any agent that can contribute to tumor formation is referred to as a carcinogen
Chemical Carcinogens classified into three groups:
Genotoxins, can initiate carcinogenesis by causing a mutation.
Cocarcinogens, by themselves cannot cause cancer but potentiate carcinogenesis by
enhancing the potency of genotoxins.
Tumor promoters, enhances tumor formation when given after exposure to genotoxins
Physical Carcinogens
Can occur through induction of inflammation and cell proliferation over a period of time
or through exposure to physical agents that induce DNA damage.
Chronic nonhealing wounds, burns, and inflammatory bowel syndrome have all been
associated with an increased risk of cancer.
H pylori infection is associated with gastritis and gastric cancer, and thus, its
carcinogenicity may be considered physical carcinogenesis.
Infection with the liver fluke Opisthorchis viverrini similarly leads to local inflammation
and cholangiocarcinoma
Induction of lung and mesothelial cancers by asbestos fibers and nonfibrous particles
such as silica are other examples of foreign body-induced physical carcinogenesis
Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide
bases and cross-linking, and DNA single- and double-strand breaks (DSBs)
Viral Carcinogens
Increase the risk of malignancy through several mechanisms:
Direct transformation
Expression of oncogenes that interfere with cell-cycle checkpoints or DNA repair
Expression of cytokines or other growth factors
Alteration of the immune system.
Clinical Manifestations
7 Danger signals of Cancer (Direct Manifestations)
1. Change in bowel or bladder habits
2. A sore that does not heal
3. Unusual bleeding or discharge
4. Thickening or lump in breast or elsewhere
5. Indigestion or difficult in swallowing
6. Obvious change in wart or mole
7. Nagging cough or hoarseness
Indirect or Systemic Manifestations
Secondary to Metastasis
◦ Cachexia
Secondary to none Metastasis
Ectopic production
Secretion of unidentified, hormone like substances
Toxic substances
Autoimmune
DIAGNOSIS OF CANCER
Clinical History
Warning signs of Cancer
1. weight loss
2. loss of appetite
3. Bleeding or discharge from a body orifice or nipple
4. Sore that is slow to heal
5. Persistent cough or wheeze
6. Change in voice
7. Difficulty swallowing
8. Change in bowel habit
9. Growing lump in skin, breast, abdomen or muscle
Physical Examination
Palpable masses (movable, non movable)
LN enlargement
Laboratory Examination
Blood examination
Radiologic procedure:
Xray, esophagoram, Barium enema, mammography, thyroid scan, CT scan, MRI
Endoscopy:
Bronchoscopy, esophagoscopy, gastroscopy, proctosigmoidoscopy, colonoscopy,
cystoscopy
Biopsy
Types:
◦ Needle biopsy (cytological)
◦ Incisional biopsy
◦ Excisional biopsy
◦ Rapid frozen biopsy/ exfoliative cytology (Pap smear)
Clinical Staging of Cancer
TNM:
Stage I = cancer confined to its primary site
Stage II = more locally advanced disease
Stage III = metastasis to regional LN
Stage IV = metastasis to distant sites
Cancer treatment
Goals of therapy:
◦ Vary with extent of cancer:
1. Localized w/o evidence of the cancer
Eradicate the cancer and CURE THE PATIENT
2. Spread beyond the local site:
Control patient’s symptoms and to maintain maximum activity for the longest
possible period of time.
Criteria of incurability:
1. Distant metastasis (most common)
2. Evidence of extensive local infiltration of adjacent organs or structures.
Surgical Management of Primary
Tumors
Goal of surgical therapy for cancer is to achieve oncologic cure
Operability of primary tumors is best determined before surgery with appropriate
imaging studies that can define the extent of local-regional disease
On occasion, primary tumors with distant metastasis are resected for palliative reasons,
such as improving the quality of life by alleviating pain, infection, or bleeding.
SURGICAL RESECTION
Surgical Curative Resection
◦ Wide local resection
◦ Low grade malignancy
◦ Basal Cell CA of the skin
◦ Radical local resection
◦ High grade malignancy
◦ En Bloc LN dissection for breast, esophagus, gastric, colorectal CA
Surgical Palliative Resection
◦ To relieve symptoms
◦ To prolong a useful comfortable life
◦ Gastrojejunostomy, colostomy
RADIOTHERAPY
Destroy tumor with preservation of anatomic structures
Direct toxic effect to cells due to ionization of water
CHEMOTHERAPY
Antimetabolites:
◦ Inhibit enzymes of nucleic acid synthesis
◦ Methotrexate and 5-FU
Alkylating agents:
◦ Substitute alkyl group for the hydrogen atom
◦ Alkylation of DNA molecule interferes with replication in transcription
Antibiotics:
◦ From soil fungi
◦ Forms stable complexes with DNA and inhibit synthesis of DNA and RNA
◦ Actinomycin D, Doxorubicin, Bleomycin
Vinca Alkaloids:
◦ Bind to microtubular proteins necessary for cell division causing cell death during
mitosis
◦ Vincristine and Vinblastine
Targeted therapies
Directed at the processes involved in tumor growth rather than directly targeting the
tumor cells
Most biologic agents are cytostatic, not cytotoxic.
Combination therapy mixing new biologic agents with either established
chemotherapeutic agents that have synergy or with other biologic agents is more likely
to lead to cancer cures
IMMUNOTHERAPY
Inhibit proliferation of cancer cells w/o affecting function of normal cells
Stimulates the host to generate specific immune response to its tumor-vaccine from
tumor cells
TUMOR SPECIFIC ANTISERUM
◦ Murine monoclonal antibodies
◦ Immunotoxins
Non- specific immunotherapy = BCG vaccine
PROGNOSIS
DETERMINANTS:
◦ Site of origin of primary tumor
◦ Stage of the disease
◦ Histologic features of the cancer
◦ Host immune factors
◦ Age of the patients
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