TRANS #12, EXAM #1

Surgical Oncology and Breast Biopsy

VARIOUS PRECEPTORS
02/26/2019
SURGERY

OUTLINE 7 Ovary 5.7

I. Introduction to Surgical IV. Other Modes of Treatment 8 Stomach 4.7
Oncology A. Chemotherapy 9 Corpus Uteri 4.6
A. Role of Surgeon in Cancer B. Hormonal Therapy 10 Leukemia 3.8
Management C. Immunotherapy and
B. What surgeons need to Targeted Therapy Estimated Ten Leading Cancer Sites in 2010 for Males in the
know D. Gene Therapy Philippines
C. Incidence and Mortality V. Radiation Therapy # Type of Cancer No. of Reported Cases
II. Cancer Etiology VI. Cancer Prevention 1 Lung 8,143
A. Definition of Cancer A. Prevention 2 Liver 5,156
B. Etiology B. Diagnosis 3 Colorectal 2,982
C. Cancer Genetics C. Treatment 4 Prostrate 2,491
D. External and VII. Breast Biopsy 5 Stomach 1,783
Environmental Influence A. Breast Examination 6 Leukemia 1,596
III. Roles of Surgery in Cancer B. Breast Bipsy 7 Brain/Nervous System 1,173
Therapy C. Core Needle Biopsy 8 Pharynx 1,065
A. Prevention Procedure 9 Non-hodgkin’s 924
B. Diagnosis Quick Review
10 Lip/Oral Cavity 778
C. Treatment Summary of Key Terms
Mnemonics Estimated Ten Leading Cancer Sites in 2010 for Females in the
Review Questions Philippines
References # Type of Cancer No. of Reported Cases
Appendix 1 Breast 11,524
2 Cervix Uteri 4,544
I. INTRODUCRTION TO SURGICAL ONCOLOGY 3 Lung 2,500
A. ROLE OF SURGEON IN CANCER MANAGEMENT 4 Colon/Rectum 2,403
• Responsible for the initial diagnosis and management of solid 5 Ovary 2,031
tumors 6 Liver 1,684
7 Corpus Uteri 1,650
® Performs biopsy (ASHMPH 2020, 2021)
8 Leukemia 1,416
• Responsible for the definitive surgical therapy of cancer patients 9 Thyroid 1,387
• Coordinates the multidisciplinary care and determines the best 10 Stomach 1,126
sequence of therapy of cancer patients
® The captain of the ship (ASMPH 2020, 2021) Five Leading Causes of Cancer Deaths in Males in 2010
# Type of Cancer No. of Reported Cases
B. WHAT SURGEONS NEED TO KNOW 1 Lung 6,475
2 Liver 4,760
• Epidemiology 3 Colon/Rectum 1,567
• Etiology 4 Leukemia 1,318
• Staging 5 Prostrate 1,290
® Treatment options and best treatment are based on the stage of
the disease
Five Leading Causes of Cancer Deaths in Females in 2010
• Natural history # Type of Cancer No. of Reported Cases
® To determine what will happen if treatment will not be given 1 Breast 4,085
® Suppose a Breast Cancer patient comes to you, Stage 4, with 2 Lung 2,043
an ulcerating mass. If you don’t give any treatment, you should 3 Cervix uteri 1,856
know what will happen to the patient. Or if the patient comes to 4 Liver 1,598
you at Stage 1, you should know what will happen if you don’t 5 Colon/rectum 1,272
give any treatment.
® Know the timeline – how long are they going to live? T/N: Lists above are based on 2010 data. New data regarding this
will come out in 2020.
• Adjuvant therapy
® Treatment given after surgery
® Ex. Chemotherapy, radiation II. CANCER ETIOLOGY
• Understanding the principles of Molecular Oncology
A. DEFINITION OF CANCER
• Cancer is a group of diseases in which cells grow and multiply out
C. INCIDENCE AND MORTALITY of control, leading to formation of tissue with abnormal form and
• Incidence function
® Number of new cases occurring • Manifested clinically as tumor masses
® Usually expressed as number of cases per 100,000 persons per • Cancer can affect practically all tissues in the body
year
• >100 types of cancer identified
• Mortality
• The result of multiple genetic alterations, leading to abnormal
® Number of deaths occurring
regulation of cell growth and reproduction
® Usually expressed as number of deaths per 100,000 persons
• Basic event/phenomenon in cancer is uncontrolled proliferation of
per year, for a particular cancer
cells
Estimated Ten Leading Cancer Sites for Both Sexes
# Type of Cancer Rate per 100,000 B. ETIOLOGY
1 Breast 31.9 • Genetics
2 Lung 17.4 ® Basic mechanism of cancer
3 Cervix Uteri 11.7 ® Accumulation of mutations in chromosomes that leads to
4 Liver 10.6
selection of cells with increasingly aggressive behavior
5 Prostrate 10.1
6 Colon/Rectum 8.8 • External/environmental influences

Trans
Group #8: Belmonte, Espiritu, Floro, Gamboa Garingalao, Tugonon 1 of 12
#12
 ® Physical
® Chemical
® Viral
® Hormonal

C. CANCER GENETICS
Normal Cell Cycle

Figure 2. Cellular Oncogene Function. This shows the different factors that
contribute to the events that occur in the cell cycle. (Bustos, 2020)

Summary of Actions
• Proto-oncogenes
® Normal genes contributing to cell proliferation and survival
• Proto-oncogenes are converted to c-oncogenes by gain-of-
function mutations
® C-oncogenes arise either by viral infections or by exposure
to carcinogenic agents
• Tumor suppressor genes prevent the occurrence of cancer by loss-
of-function mutations
• Presence of oncogenes or absence/inactivation of tumor suppressor
genes can lead to cancer
Five Mechanisms of Converting Proto-oncogenes into
Oncogenes
Figure 1. Regulation of Cell Cycle. Replication with fidelity and organization is • Point mutation
an essential function of all living tissue for survival. (Bustos, 2020)
® Abnormal hyperactive protein
• The cell cycle gives every living organism the ability to replicate itself • Gene amplification
to maintain normal form and function. ® Excess normal protein
• Done with extreme integrity and organization to ensure survival • Chromosomal translocation
• Phases of cell division: ® Excess normal protein or abnormal hyperactive protein
® G1 phase – Gap phase • Local DNA re-arrangements
® S phase (synthesis phase) ® Abnormal hyperactive protein
® G2 phase (protein synthesis including microtubules) • Insertional mutagenesis
® M phase: where cells divide (mitotic phase) ® Excess normal protein
® G0 phase – quiescent phase
Mechanism of Cancer Genetics
• Proto-oncogenes
® Normal genes
® 23 pairs of chromosomes
• Oncogenes
® Mutated forms of proto-oncogenes that, when expressed, lead
to tumorigenesis
® Mutations are dominant because it only has to mutate a single
allele for them to be expressed
Functions of Cellular Oncogenes: 4 Types of Proteins Produced
Type Protein Function
Growth Factors PDGF, EGF, FRF1-7, IGF1/2, TGF- Initiates process
alpha, TGF-beta of cell replication
Growth Factor EGFR, PDGFR, FGRG, RET
Receptors
Signal Tyrosine Kinase (SRC, LYK, SYN),
Tranducers Other signaling proteins (RAF, MOS, Figure 3. Five Mechanisms for converting Proto -oncogenes to Oncogenes.
COT), G Proteins (RAS, GSP, GIP) (Bustos, 2020)
Nuclear MYC, FOS, JUN Seen inside
Factors every cell Types of DNA Rearrangements
• Deletion
• Tumor suppressor genes • Insertion
® Normal genes that control cell division, mediates repair of DNA • Transposition
damage and apoptosis • Inversion
® Mutations are recessive because it has to inactivate both alleles
for it to lose function

Figure 4. Types of DNA Rearrangements. (Bustos, 2020)

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 Genetic Alterations • Loss of function by tumor suppressor genes
• Mutations/alterations in genes
• 2 types of gene involved in cancer after mutation: germline and Overview of Carcinogenesis
somatic • The hallmarks of cancer
• Germline Mutated Genes • Self-sufficiency of growth signals
® Can be inherited and are • Insensitivity to inhibitory signals
® Already incorporated in the normal genes in the chromosomes • Evasion of apoptosis (programmed cell death)
• Somatic Mutated Genes • Potential for limitless replication
® Acquired mutation (from carcinogens such as sunlight, random • Sustained angiogenesis
chances leading to DNA damage, etc) • Tissue invasion and metastasis

Figure 7. Overview of Carcinogenesis. DNA is exposed to carcinogenic factors

(e.g. infectious agents, radiation, heredity). Oncogenes are activated
Figure 5. Genes, when mutated, are associated with certain cancers. BRCA1 and such activities accumulate to result to the hallmarks of cancer.
and BRCA2 are genes associated with breast cancer. Colon cancer is (Bustos, 2020)
associated with the APC gene. (Bustos, 2020)
Cancer Development is a Multi-Stage Process
• On figure 5, common tumor suppressor genes mentioned by doc:
• Begins with a mutation in a single cell and continues down the cell
® APC gene: associated with colorectal tumors and produced FAP line
syndrome
• Disease of clonal progression
® BRCA1 and BRCA2: when mutated, they render a predisposition
to the development of breast and even, ovarian cancer ® E.g. 5 oncogenes involved in colorectal cancer (5 hits until a
cancerous tissue is formed)

Figure 8. Cancer as a Multistage Process (Bustos, 2020)

Human Genome
• A complete human genome has already been mapped out
• 3 billion base pairs of DNA
• 46 chromosomes (23 pairs)
• At least 40,000 genes
• ~100 oncogenes
• ~40 tumor suppressor genes
Hereditary Cancer
• Suspect hereditary forms of cancer if the following are present:
• Tumor at much younger age than usual
® e.g. Breast cancer onset in 20 year old
• Bilateral disease
• Multiple primary malignancies
• Presence of cancer in a less affected sex
® e.g. Breast cancer in a male
Figure 6. Molecular Basis of Cancer. A normal cell could be exposed to • Clustering of the same cancer type amongst relatives
damaging agents leading to DNA damage. When left unrepaired, • Occurrence of cancer with other conditions
mutations can occur in cells leading to the development of cancer. End
result of this process is the development of tumors, malignancy, or Most Commonly Encountered Hereditary Cancer Syndromes
simply, cancer. (Bustos, 2020) RB1: Hereditary Retinoblastoma
• Pediatric retinal tumor
Cancer Genetics
• RB1 gene encodes for the Rb protein
• Accumulation of mutations
® Transcription regulator
• Gain of function by oncogenes
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 ® Controls the cell cycle, differentiation, and apoptosis ® You are definitely going to have it
• Penetration is dominant but there are hereditary and non-hereditary • APC functions in:
forms ® Cell-cell interactions
® Hereditary: You already have the RB gene and just one ® Cell adhesion
somatic mutation results to malignancy ® Down regulation of beta-catenin
® Non-hereditary: Needs two somatic mutations (two-hit ® Maintenance of cytoskeletal microtubules
hypothesis) • Genotype-phenotype correlation
• Other manifestations:
P53: Li Fraumeni Syndrome (LFS)
® Gardner’s syndrome – congenital hypertrophy of retinal pigment
• p53 gene epithelium, desmoid tumors, epidermoid cysts, osteomas
® Tumor suppressor gene ® Turcot’s syndrome – CNS system
® Most commonly mutated gene associated with cancer ® Tumors, ex. Medulloblastoma
® p53 protein – transcription factor for cycle arrest and
apoptosis in DNA damage HMLH and hMSH2: Lynch Syndrome
® 70% of LFS patients: with germline mutation in p53 • T/N: These were mentioned in passing
® 30% of LFS patients: maybe due to genetic alterations in other • Mismatch repair genes and hereditary nonpolyposis colorectal
proteins that interact with p53 cancer: hMLH1 and hMSH2
• Cluster of malignancies in one family: • Autosomal dominant
® Early onset breast cancer • Amsterdam criteria used to diagnose patients with this syndrome
® Soft tissue sarcomas ® 3 or more relatives with an HNPCC-associated cancer
® Brain tumors (colorectal, endometrial, small bowels, ureter, renal pelvis),
® Adrenocortical tumors one of whom is a first-degree relative of the other two
® Leukemia ® At least 2 successive generations affected
• Criteria for classic LFS ® At least 1 case diagnosed before age 50 y/o;
® T/N: This criteria as well as Figure 9 were not in doc’s ppt but familial adenomatous polyposis excluded
were adapted from 2021’s trans
Other Cancer Syndromes
® Bone of soft tissue sarcoma when younger than 45 years Gene Syndrome Organs Involved Gene
® A first degree relative with cancer (mentioned above) before 45 Function
years PTEN Cowden Trichilemmomas, Negative
® Another first or second-degree relative with either a sarcoma (Phosphate and Disease benign tumors of the feedback on
diagnosed at any age OR any cancer diagnosed before age 45 tensin hair follicle, PI3k signaling
homologue) infundibulum, pathway
mucocutaneous
papillomatosis, breast
and thyroid CA
P16 Hereditary Melanoma, pancreatic Tumor
Malignant CA suppressor
Melanoma
E-Cadherin Hereditary Autosomal dominant, Cell adhesion
(CDH1) Diffuse 70-80% chance to
Gastric have a gastric CA;
Cancer Lobular breast CA
RET MEN2 MEN2A: Medullary Proliferation,
(Transmembrane thyroid carcinoma, migration and
receptor tyrosine pheochromocytoma, differentiation
kinase) parathyroid adenoma of cells from
the neural
MEN2B: Medullary crest
thyroid carcinoma,
marfanoid habitus,
mucosal neuromas,
ganglioneuromatosis

D. EXTERNAL AND ENVIRONMENTAL INFLUENCE

• Carcinogens
® Any substance that contributes to tumor formation
Figure 9. Percentage of tumors exhibiting mutations in the most mutated gene, § 3 types: physical, chemical, viral
p53 in human cancers. Top 5: esophagus, ovary, colorectal, head and
neck, and pancreas. (Bustos, 2019). Chemical Carcinogens
BRCA1 and BRC2: Hereditary Breast-Ovarian Cancer Syndrome • Genotoxins
• #1 cancer in the Philippines is breast cancer ® Substances that cause direct damage to DNA producing
• Involved in homologous recombination of DNA repair mutations
• Co-carcinogens
• Not all breast cancers are caused by these genes
® Do not cause damage alone, but in combination with other
® Only 5-10% of breast cancers are hereditary
carcinogen, they can further promote tumor formations
• Increases the risk of breast, ovarian, prostate, and colon cancer
• Tumor promoters
• Mutations in these genes account for 80% of the familial cases of
® Enhance tumor formation after exposure to genotoxins
breast cancer
• Cumulative risk: the risk of getting the cancer List of Known Chemical Carcinogens
® By age 70, patients have an 84% cumulative risk of having Predominant Tumor
Chemical
breast cancer and 27-44% for ovarian cancer Type
• Angelina Jolie carried one or two of these genes and had a Estrogen Replacement Therapy
Endometrial Cancer
prophylactic mastectomy to prevent the occurrence of breast cancer Tamoxifen
Breast Cancer Estrogen Replacement Therapy
APC: Familial Adenomatous Polyposis (FAP) Syndrome
• Multiple colonic and rectal polyps, which appear during Nasal CA Nickel
adolescence and progress to cancer Brain Tumors Vinyl Chloride
• Lifetime risk at age 50 is 100%
Oncology 13.12: SURGICAL ONCOLOGY AND BREAST BIOPS 4 of 12
 Lymphatics and
Vinyl Chloride • Both DNA and RNA viruses are associated with human cancer
Hematopoietic System
Soft Tissue Sarcoma TCDD (Tetrachlorodibenzo-p-dioxin)
Lung CA, Oral CA,
Pharyngeal CA,
Esophageal CA, Tobacco: number 1 carcinogen
Pancreatic CA, Renal Cell
CA, Cervical CA
Aflatoxin
Liver Cancer Tobacco
Vinyl Chloride
Arsenic
Skin Cancer
Coal Tar
Benzene, Cyclophosphamide,
Leukemia Figure 10. 1910 Peyton Rouse Experiment (Bustos, 2020)
Chlorambucil, Ethylene Oxide
Benzidine, Tobacco, RNA Viruses (Retrovirus)
Bladder CA
Cyclophosphamide • Mechanism: Genomic integration into the host genome
Cadmium, Tobacco, Chromium (VI) • RNA of the virus is incorporated/ transcribed → DNA provirus are
Lung CA
compounds, Nickel transferred on to the next line of cells → becomes part of host
Nasopharyngeal CA Chinese-style salted fish chromosome integration
Scrotal CA Coal tar
Vaginal and Clear Cell
DES
Adenocarcinoma
Lymphoma Ethylene Oxide

Physical Carcinogens
• Agents that produce DNA damage through the induction of:
® Inflammation
® Proliferation
® Chronic irritation
• Conditions that predispose to chronic inflammation and irritation:
® Non-healing wounds
® Foreign body-induced
§ e.g., asbestos leading to lung cancer or mesothelioma
® Burns
§ Associated with squamous cell carcinoma
® Inflammatory bowel disease
§ Associated with colon cancer
• Infectious agents
® Parasites
§ Clonorchis sinensis, Opisthorchis viverrrini
- Can predispose to cholangiocarcinoma
® Bacteria
§ H. pylori Figure 11. Integration of a Retrovirus inside a Host Cell (Bustos, 2020)
- Can predispose to gastric cancer
• Radiation DNA Virus
® Best known physical carcinogen • Causes 80% of human cancer of viral etiology
® Causes DNA damage directly in the form of: • No direct genomic integration into the host genome or
§ Nucleotide changes, single and double strand breaks chromosome but cause direct injury thus increasing
® Has 2 forms: opportunity for mutations
® Ionizing radiation - associated with thyroid cancer • E.g. Hep B hepatocellular carcinoma (Hepadnavirus family)
- X-rays (most common) ® Hepatocellular injury secondary to T-cell immune response in
- Gamma rays the liver cells → chronic persistent hepatitis → triggers
- Alpha particles proliferative response → increase opportunity to mutations →
- Beta particles Hepatocellular carcinoma
§ Non-ionizing radiation (UV) - association with skin cancer List of Known Viruses that Cause Cancer
- UV rays from sunlight (most common) Virus Tumor Type
Burkitt’s Lymphoma
Foreign Body Carcinogens
Hodgkin’s Disease
• Mechanism: Produce deletions and translocation in the EBV Immunosuppression-related Lymphoma
chromosomes Sinonasal angiocentric T-Cell Lymphoma
• Mineral fibers: can predispose to mesothelioma Nasopharyngeal CA
® Asbestos HBV Hepatocellular CA
® Silica HCV Hepatocellular CA
Kaposi’s Sarcoma
Viral Carcinogens HIV Type 1
Non-Hodgkin’s Lymphoma
• 1910: Peyton Rouse experiment on chickens with sarcoma
Cervical CA
® Chicken with sarcoma → extract obtained from this sarcoma → HPV 16 and 18
Anal CA
extract injected to another chicken → recipient chicken HTCLV Adult T-Cell Leukemia/Lymphoma
developed cancer
® Oncogenic Virus: Rous Sarcoma Virus Hormonal Carcinogens
§ the first cancer-causing virus discovered (ASMPH 2020 • Drivers of cell division in target organs
trans, 2018)
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• Estrogen and Progesterone Types of Oncologic Resection
® Either exogenous or endogenous • R0
® Influences the development of breast and endometrial cancer ® Resection with microscopically negative margins
® No tumor left behind
III. ROLES OF SURGERY IN CANCER THERAPY • R1
A. PREVENTION ® Resection with microscopically positive margins
• R2
Multiple Polyposis of the Colon
® Resections with grossly positive margins
• Approximately 1⁄2 will develop colon cancer by the age of 40
® Tumor definitely left behind
® At the age of 70, 100% will develop colon cancer • Determined after histopathology
® (+) APC gene
• Total colectomy is recommended before age 20 Radical Surgery versus Conservative Surgery
• Removal of the colon has its complications but this has to be • Breast
weighed against the development of cancer
® Radical Mastectomy
Familial Breast Cancer § Removal of breast, axillary lymph nodes, pectoral muscles
• Approximately 60-80% will develop breast cancer in their lifetime ® Modified Radical Mastectomy
§ Only the breast and axillary lymph nodes are removed;
® (+) BRCA1 or BRCA2
The muscles are spared.
• At the age of 80, incidence of breast cancer rises to around 85%.
® Breast Conservation Surgery
• Prophylactic bilateral mastectomy is recommended
§ Removal of the tumor and some axillary lymph nodes
® Can still be cosmetically preserved
• Soft Tissue Sarcoma
® Amputation
Medullary Carcinoma
® Compartmental Resection
• (+) MEN2B
§ Removal of muscle groups and the tumor
• Should undergo total thyroidectomy within the age of 5 years old.
® Wide Excision
B. DIAGNOSIS § Removal of tumor
§ What is done now, as long as the margins are negative.
Needle Biopsy
Surgical Management of Regional Lymph Nodes
• Fine Needle Aspiration Biopsy (FNAB)
• Most of the surgeries are designed to remove the primary tumor
® Aspiration of cells and tissue fragments through a needle that
has been guided into the suspect tissue and the regional lymph nodes
® Preferred biopsy for thyroid nodules Purpose of Lymph Node Dissection
• Core Needle Biopsy • For staging and prognosis
® A core of tissue is obtained through a specially designed needle • To decrease local recurrence
introduced into suspect tissue • To improve survival rate
® Involves a bigger needle (gauge # 14, 11 or 8)
® Preferred biopsy for breast lesions Sentinel Lymph Node Biopsy
• The first node coming from the breast or other organs is identified
Open Biopsy using a special blue dye (e.g. isosulfan blue, patent blue V, or
• Incisional Biopsy methylene blue) or a radionuclide.
® Removal of a small wedge of tissue from a larger tumor mass • Sentinel node
(“a piece”) ® First node to receive drainage from the tumor
® Preferred method of diagnosing soft tissue and bony sarcomas ® If negative, no need for axillary dissection
§ For large lesions ® If positive, need to do axillary dissection
• Excisional Biopsy • Isosulfan blue dye and Tc labeled sulfur colloid or albumin are
® Removal of the entire suspected tumor tissue (“everything”) the substances used to identify the sentinel node
® Preferred method of diagnosing small lesions (e.g. small ® Inject dye around the tumor and wait for the first node to
melanomas) “light up”
® Both diagnostic and therapeutic
Surgical Management of Distant Metastasis
REVIEW: • In general, surgical therapy is not indicated for metastatic
• FNAB – biopsy of thyroid nodules disease
• Core needle biopsy – Biopsy of breast lesions • However, it has resulted in cure in some cases of isolated
• Incisional biopsy – Soft tissue sarcomas metastases to the liver mainly from the colon
• Excisional biopsy – Small lesions
Reconstruction and Rehabilitation
C. TREATMENT • To reconstruct anatomic defects to substantially improve function
and cosmetic appearance
Surgical Management of a Primary Tumor ® E.g. post mastectomy, the breast can be reconstructed again.
• The goal of surgical treatment for cancer is to achieve oncologic
cure by removing the whole tumor IV. OTHER MODES OF TREATMENT
• Oncologic operations should achieve microscopically negative A. CHEMOTHERAPY
surgical margins by removing a normal rim of tissue in malignant • Systemic administration of anti-cancer drugs
tumors
® Can be given oral, IV, IM, or SC
® No tumor left behind
• Goals:
® Decrease and prevent systemic recurrence
Curative vs Palliative Resection
§ You have to prevent systemic recurrence in those patients
• Curative Resection which had surgery already
® Resection of tumor with microscopically negative margin ® Decrease tumor burden
• Palliative Resection § For those patients who cannot have surgery because the
® Done to improve quality of life by alleviating pain, infection, tumor is too large for you to resect and close; shrink the tumor
bleeding, and mechanical effects of the tumor ® Treat micromtastasis
® Purpose is not to cure but to improve quality of life • These drugs circulate throughout the entire body

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 ® Because of this, drugs can cause toxic effects to other organs § To decrease risk of recurrence/relapse
which is not the primary tumor § To improve survival
• Regional administration to reduce systemic toxic effects (2021 Trans) ® Given in addition to surgery to further increase the protection of
® Hepatic artery infusion for liver cancer the patient
® Intraperitoneal infusion for peritoneal metastasis • Neoadjuvant
• First order kinetics ® Can be given pre-operatively to allow the tumor burden to be
® Chemotherapy usually kills this way decreased
® With the administration of the drug, a constant percentage of ® Done in patients with huge tumor loads which we cannot resect
cells are killed and close even with flaps or grafts
§ Killing by percentage, not by number ® Can be given even if the tumor is small to assess tumor
® Example: Every cycle will remove 10% of the initial tumor response (2021 Trans)
burden, not 1000 cells per cycle - e.g. If a limb is amputated, we can no longer determine if
• Chemotherapy can target specific areas of the cell cycle, but a drug will work if it is only given after surgery.
some are also non-specific § Advantages:
® Classification: - Decrease tumor burden/size
§ Cell-cycle phase specific - Treatment without delay of post-op recovery
- Can only kill in a specific part of the cell cycle - Assess tumor’s response clinically and pathologically
§ Disadvantages:
- Increasing the dose will not increase the cell kill
§ Cell-cycle phase non-specific - Patient selection
o There is a need to see if the tumor is really
- In any cell cycle stage
chemosensitive or not which can delay treatment for the
- Linear dose-response relationship patient
o Fraction of cells killed increases with increases in - Problems with tumor localization, margin analysis,
dose pathologic staging, lymphatic mapping
• For class, know the representative drug and the usual side effect o Sometimes if you give chemotherapy and the tumor
it entails so you can anticipate what to do prior to it happening completely disappears, then you don’t have anything
to give to the pathologist
Non-Cell Cycle Specific Chemotherapeutic Drugs
o Without the tumor, you can’t do TNM staging
• Alkylating agents
- No significant difference in rates of infection, necrosis
® Classic between pre- or post-surgery chemotherapy
® Nitrosoureas • Combination Chemotherapy
® Miscellaneous DNA-binding agents
® Synergistic
® MOA: Direct damage to DNA by damaging the cross linking of ® Different dose limiting toxic effects
the strands of the DNA helix à apoptosis of cancer cell § Maximize cellular toxicity that can be tolerated by the host
• Antitumor antibiotics ® Different resistance patterns/delays resistance
® MOA: Interfere with DNA and RNA synthesis § Avoid resistance brought about by constantly mutating and
Cell Cycle Specific Chemotherapeutic Drugs unstable cancer cells
§ There is a larger tumor size which is heterogenous
• Antimetabolites
® Broader coverage in heterogeneous population
® Folate analogue: methotrexate
® Purine analogue: 5-FU Drug Resistance
® Pyrimidine analogue: ara-C • Genetically unstable mutating tumor cells
® Ribonucleotide reductase inhibitor: Hydroxyurea • Large tumor size
® MOA: Substitute purine and pyrimidine analogs (nucleic ® Competition for oxygen (large gets more oxygen, small gets
acid synthesis) during the S-Phase hypoxic)
§ Effecitive in those with high growth fraction • Adaptive response
§ Tries to act like an analog to structurally or naturally
® Breast cancer patients can convert from HER2 (+) to (-) after
ocurring metabolites in your DNA
operation
§ Inhibits enzymes in nucleic acid synthesis
• Plant alkaloids General mechanisms of drug resistance
® Vinca alkaloids Mechanism of Resistance
® Epipodophyllotoxin • Decreased drug accumulation (influx, efflux)
® MOA: Blocks microtubule polymerization during the M- • Decreased drug activation
Phase to impair mitotic spindles • Increased inactivation of drug or toxic
• Taxanes Cellular and intermediate
• Miscellaneous: Biochemical • Increased repair of drug-induced damage to
® Asparaginase Mechanisms DNA, proteins, membranes
® Estramustine • Alteration of drug targets
® Mitotane • Alteration of cofactor or metabolite levels
• T/N: Doc Flashed a table of drugs under each classification of • Alteration of gene expression
chemotherapeutic agents. Please see appendix for the full table • Pharmacologic and anatomic drug barriers
(tumor sanctuaries)
Ways of Giving Chemotherapy
• Host-drug interactions
• Chemotherapy can be given as primary treatment or as adjuvant Mechanisms o Increased drug inactivation by normal
treatment relevant in tissues
• Primary vivo o Decreased drug activation by normal
® Sometimes when the patient already has distant metastasis, you tissues
just primary palliative treatment o Relative increase in normal tissue drug
® This is your primary chemotherapy, which is the main treatment sensitivity (toxicity)
for your patient Host-tumor
• Adjuvant inteactions
® For patients with no distant disease or metastasis Drug Toxicity
® “In addition” to the treatment already given • Bone marrow suppression
® Postoperatively given ® Medical oncologist always checks the complete blood count
§ To eradicate micrometastasis before they do the next chemotherapy
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• Stomatitis ® Advantages
• GIT ulceration § Minimize seeding in the area where you will be doing the
• Alopecia surgery
® Because chemotherapy usually hits cells with high growth fraction § Make inoperable operable
which are constantly dividing ® Disadvantages
§ Ex. Hair, nails, GI, bone marrow § Wound healing problems
• Assess patient before proceeding with the next chemotherapy - A problem since you make the tissue hypoxic when you
irradiate à healing problems
B. HORMONAL THERAPY - Problematic for poorly vascularized areas (2021 Trans)
• Estrogen receptor antagonists § Subsequent RT in positive margins post operatively
• Progesterone receptor antagonists - Issue: Can you give RT again, especially if nothing else can
• Positive staining for the receptors can be determined after core be surgically removed?
needle biopsy of the tumor o There is a limit to how much radiation you can give again
® With this you will know if the patient needs hormonal treatment • Post-operative
after surgery or not ® Advantages
• Block or replace a certain hormone (2021 Trans) § Proper histologic evaluation
• Best known for breast and prostate cancers - Margins can be properly assessed
§ RT modified on the basis of margin status
C. IMMUNOTHERAPY AND TARGETED THERAPY ® Disadvantages
§ Larger radiation does due to contamination in surgery
Targeted Therapy - Contamination when moving around structures in surgery
• Exploit the molecular differences between the cancer cell and the § Less radiosensitive due to hypoxia
normal cell - Since vessels are cut off during surgery
® One example is targeting the tumor growth § Post-op adhesions expose more bowels to radiation
• The ideal target will be those responsible for proliferation and - Crucial for pelvic irradiation
survival •• Chemo can be given before or concurrently with radiation
• Basic principle is molecular interference and development of anti- • (chemosensitizers)
cancer cells (2021 Trans) • Side effects of radiation therapy can be quite long
• For the breast, we use HER2, which is a receptor on the surface of ® Sometimes the changes can be in the first 2-3 weeks, but it can
the cancer cell be as long as several years afterwards
® You can give Trastuzumab to supress this ® Usually you see desquamating or erythematous burned skin
• Gleevec and Imatinib can be used for patients with CML or GIST •• Acute changes are within 3 weeks, mostly comprised of burns;
tumors chronic changes are beyond 3 weeks, mostly comprised of
fibrotic changes (2021 Trans)
Immunotherapy
• Based on the ability of the immune system to recognize tumor- Local Effects of Radiation (Table 10-13 from Harrisons)
associated antigens present on cancers and to direct cytotoxic Organ Acute Changes Chronic Changes
responses through humoral or T cell mediated immunity Erythema, wet or dry Telangiectasia,
® e.g. Give interleukin to stimulate T-cells and NK cells Skin desquamation, subcutaneous
® e.g. Give antigens to allow the body to mount an immune epilation fibrosis, ulceration
response (same principle as vaccination) and give antibodies Nausea, diarrhea, Stricture, ulceration,
• Types: GI Tract edema, ulceration, perforation,
® Nonspecific hepatitis hematochezia
® Antigen specific - Nephropathy, renal
Kidney
• Not yet the part of the core treatment of cancer but can be added if insufficiency
you have money Dysuria Hematuria,
• It’s like giving vaccines; you activate your immune system to fight Bladder ulceration,
these cancer cells perforation
Sterility Atrophy, ovarian
Gonads
D. GENE THERAPY failure
• Replacement or deletion of tumor suppressor genes to enhance Lymphopenia, Pancytopenia
Hematopoietic
immune response to cancer cells neutropenia,
tissue
• Not available in the Philippines thrombocytopenia
• The problem here is choosing the ideal vector to introduce the viruses Epiphyseal growth Necrosis
Bone
which can enhance or suppress these tumor suppressor genes arrest
Lung Pneumonitis Pulmonary Fibrosis
V. RADIATION THERAPY - Pericarditis, vascular
• Gray (Gy) is the unit used to measure the total about of radiation the Heart
damage
patient is exposed to Upper Mucositis, xerostomia, Xerostomia, dental
• Involve the application of x-rays or gamma rays to damage the DNA aerodigestive anosmia caries
of cancer cells tract
• It’s basically a local treatment that burns your tissue, unlike Conjunctivitis Cataract, keratitis,
chemotherapy which is systemic Eye
optic nerve atrophy
® You only irradiate the organ you want to irradiate; you cannot Cerebral edema Necrosis, myelitis
irradiate the whole person • Nervous System
•• Radiation Therapy Treatment Planning VI. CANCER PREVENTION
® Define target as well as dose-limiting organs in the vicinity • Primary
® Radiation simulation ® Prevention of initial cancers in healthy individuals
§ Beam distribution that will best achieve the homogeneous • Secondary
delivery of the target volume and minimize the dose to the
® Prevention cancer in individuals with premalignant conditions
normal tissue
• Tertiary
® Linear accelerators allow better focus such that only particular
® Prevention of second primary cancers in patients cured of their
organs are hit, and other structures are avoided
• Adjuvant (Pre-operative) initial disease
® Also given to reduce the tumor size prior to resection • Chemoprevention
Oncology 13.12: SURGICAL ONCOLOGY AND BREAST BIOPS 8 of 12
 ® The systemic of local administration of therapeutic agents to
prevent the development of cancer
® Examples
® Primary: Tamoxifen (as well as Raloxifene) reduces risk of
estrogen receptor-positive breast cancers by one half and
reduces the risk for estrogen receptor-positive tumors by 69% in
high risk patients
® Secondary: Celecoxib reduce polyp number and burden in
patients with FAP
® Tertiary: 13-cis-retinoic acid has been shown to reverse oral
leukoplakia and to reduce second primary tumor development in
head and neck cancers Figure 12. Normal anatomy of the breast showing the Cooper’s Ligament in
relation to the other parts of the breast. (del Valle, 2010)
A. TRENDS
• Molecular basis of treatment
® Earlier detection of cancers
® Identification of serum markers
® We do genomic testing for tumors to check whether the patient
really needs chemotherapy or radiotherapy, or neither
• More conservative surgery
® Connected with earlier detection
® Other experimental options: radiofrequency ablation,
cryoablation, heat-producing technologies (lasers, microwaves,
focused ultrasounds)
• Regional lymph node dissections Figure 13. Function of Cooper’s Ligament. With age, the tensile strength of the
® Proper detection and management, based on primary cancer, is ligament weakens causing sagging of the breast. When there is an
tumor impinging on the ligament and pulling it backwards, dimpling is
still being debated the effect. (Wikimedia, 2019)
® Spread may be related to gene expression profile
® Instead of doing automatic regional lymph node dissections, we • Palpation
do selective smaller dissections ® Location
• Individualized therapy = biologic variability within tumor groups ® Size
® The intent is to determine the underlying biology of each tumor ® Shape and Borders
to tailor accordingly § Irregularity points to a more malignant tumor
® Future: All tumors tested and treatments individualized ® Mobility
• e.g. Breast cancer in a 27-year-old is different in a 76-year-old ® Tenderness
§ Absence of such points to a more malignant tumor
VII. BREAST BIOPSY DEMO
A. BREAST EXAMINATION B. BREAST BIOPSY
• Thorough Breast Examination is initially needed to assess the • Tumors less than 1 cm in diameter are usually hard to catch and
number of breast tumors and the characteristics of each can be missed
• Inspection • Mode of biopsy will largely depend on the characteristics of the
® Symmetry lesion
® Color • Fine Needle Aspiration Biopsy would be more appropriate for
® Contour purely cystic lesions
® Lesions ® Aspiration of fluid in order for a pathologist to characterize it
§ Dimpling ® Inappropriate for solid tumors
- Normally, the breast does not sag due to it being • Core Needle Biopsy
suspended by the Cooper’s Ligament ® Most appropriate for small to medium sized solid tumors
- Coopers ligament is attached from the fascia covering • Also used when a cystic lesion has a focal solid portion
the pectoralis major, through the breast parenchyma,
and is attached to the skin
- Anything that presses on the suspensory ligament pulls
the ligament which pulls the skin, which causes the
dimpling
® Nipple Figure 14. 22 mm Needle Gun for Core Needle Biopsy. (ASMPH 2021, 2019)
§ Inversions
- Much like dimpling, nipple inversions occur due to the C. CORE NEEDLE BIOPSY PROCEDURE
tumor impinging and pulling back on whatever is • Local anesthesia is applied before core needle biopsy
attached to the back of the nipple • The needle is guided by ultrasound in order to accurately hit the
- In this case, the mamillary ducts, much like the Cooper’s lesion for sampling
Ligament mentioned earlier, is what is impinged by the • In the olden times, UTZ guided core needle biopsy was not used
tumor causing nipple inversion and often times the tumor of interest was missed
® Erythema, Erosion, Edema
§ Edema is mostly due to lymphatic obstruction by the tumor

Figure 15. Retract the metal sheath covering the needle by pressing on the
button shown above. (ASMPH 2021, 2019)

Oncology 13.12: SURGICAL ONCOLOGY AND BREAST BIOPS 9 of 12

 Figure 22. Fire the needle again in order to reset the device. (ASMPH 2021,
2019)
Figure 16. Cock the needle back by pressing on the button immediately behind
the button used to retract the needle sheath. (ASMPH 2021, 2019)
QUICK REVIEW
SUMMARY OF TERMS
• Role of Surgeon in Cancer Management
® Initial diagnosis and management of solid tumors
® Definitive surgical therapy
® Coordinate the multidisciplinary care and determine best
sequence of therapy
• Cancer
® Cells that grow and multiply out of control, leading to formation of
tissue with abnormal form and function
® Tumor masses
Figure 17. Position the needle on the desired site for biopsy. (ASMPH 2021, ® Result of multiple genetic alterations, leading to abnormal
2019) regulation of cell growth and reproduction
• Etiology
® Genetics: Accumulation of mutations
® External/environmental influences
• Mechanism of Cancer Genetics
® Proto-oncogenes: normal; contribute to cell proliferation and
survival
§ Can be converted to c-oncogenes by gain-of-function
mutations
® Oncogenes: mutated forms that lead to tumorigenesis when
expressed
® Tumor suppressor genes: Normal genes that control cell division
Figure 18. Press on the green switch to fire the cocked back needle. (ASMPH and mediate repair of DNA damage and apoptosis
2021, 2019) § Loss-off-function mutations
• Converting Proto-oncogenes into Oncogenes
® Point mutation: abnormal hyperactive protein
® Gene amplification: excess normal protein
® Chromosomal translocation: excess normal protein or abnormal
hyperactive protein
® Local DNA re-arrangements: abnormal hyperactive protein
® Insertional mutagenesis: excess normal protein
• Genetic Alterations
® Mutations
® Germline: inherited
Figure 19. Retract the needle sheath to reveal the casted tissue sample resting ® Somatic: acquired
on the needle. (ASMPH 2021, 2019) ® Accumulation of mutations
® Gain of function by oncogenes
® Loss of function by tumor suppressor genes
® Tissue specificity
• Hallmarks of cancer
® Self-sufficiency of growth signals
® Insensitivity to inhibitory signals
® Evasion of apoptosis
® Potential for limitless replication
® Sustained angiogenesis
® Tissue invasion and metastasis
Figure 20. Place the tissue sample on a slide, in this case, a piece of toilet • Human genome
paper. (ASMPH 2021, 2019) ® 3 billion base pairs of DNA
® At least 40,000 genes
® 100 oncogenes
® 40 tumor suppressor genes
• Hereditary Cancer: younger age than usual, bilateral disease,
multiple primary malignancies, less affected sex, clustering of same
cancer type among relatives
® RB1: pediatric retinal tumor
® P53: Li-Fraumeni Syndrome (most commonly mutated gene)
Figure 21. Cock the needle back again. (ASMPH 2021, 2019) § P53 is for cycle arrest and apoptosis in DNA damage
§ Cluster of malignancies: breast cancer, sarcomas, brain
tumors, adrenocortical tumors, leukemia

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 ® BRCA1 and BRCA2: #1 cancer in Philippines in breast cancer; - To decrease tumor size, treatment without delay of post-op
homologous recombination of DNA repair recovery, assess tumor’s response clinically and
® APC: multiple colonic and rectal polyps (Familial adenomatous pathologically
Polyposis) Syndrome § Combination chemotherapy
® HMLH and hMSH2: Lynch Syndrome ® Drug resistance
• External and environmental influences § Large tumor size; genetically unstable mutating tumor cells,
® Carcinogens: contributes to tumor formation adaptive response
® Chemical ® Drug toxicity
§ Genotoxins: direct damage to DNA § Bone marrow suppression, stomatitis, GIT ulceration, alopecia
§ Co-carcinogen: do not cause damage alone, can further • Hormonal therapy: Estrogen receptor antagonists, progesterone
promote tumor formations receptor antagonists
§ Tumor promotors: enhance tumor formation after exposure to • Immunotherapy
genotoxins ® Targeted therapy: molecular interference of development of anti-
® Physical cancer cells
§ Chronic inflammation and irritation predisposing conditions: ® Immunotherapy: recognize tumor associated-antigens present on
- Non-healing wounds cancers and to direct cytotoxic responses
- Foreign body-induced • Gene therapy
- Burns ® Replace or delete tumor suppressor genes to enhance immune
- Inflammatory bowel disease response to cancer cells
§ Infectious agents • Radiation therapy
- Clonorchis sinensis, Opisthorchis viverrni ® Radiation simulation, linear accelerators for better focus
- H. pylori ® Adjuvant
§ Radiation § advantages: minimize seeding, make inoperable operable;
- Ionizing radiation associated with thyroid cancer § disadvantages include poor wound healing, subsequent RT in
- Non-ionizing radiation (UV) associated with skin cancer positive margins post operatively
® Foreign body carcinogens: asbestos, silica ® Post-operative
® Viral: Rous Sarcoma virus § Advantages: Proper histologic evaluation, RT modified on
§ RNA: genomic integration into host genome basis of margin status
§ DNA viruses: 80% of human cancers; no direct genomic § Disadvantages: Larger radiation dose due to contamination in
integration into host genome surgery, less radiosensitive due to hypoxia, post-op adhesions
® Hormonal: estrogen and progesterone ® Within 3 weeks: acute changes (mostly burns), chronic beyond 3
• Roles of surgery in cancer therapy (mostly fibrotic)
® Prevention • Cancer prevention
§ Multiple Polyposis of Colon: Total colectomy is recommended ® Chemoprevention
before age 20 § Primary: Tamoxifen reduces risk of estrogen receptor positive
§ Familial breast CA: prophylactic bilateral mastectomy Breast CA
® Diagnosis § Secondary: Celecoxib reduce polyp number and burden in FAP
§ Fine needle aspiration biopsy: cells and tissue fragments; § Tertiary: 13-cis-retinoic acid to reverse oral leukoplakia and to
preferred for thyroid nodules reduce second primary tumor development in H&N
§ Core needle biopsy: core of tissue; for breast lesions ® Trends
§ Incisional biopsy: small wedge of tissue; soft tissue and bony § Molecular basis of treatment
sarcomas (large lesions) § More conservative surgery
§ Excisional biopsy: entire suspected tumor tissue (small lesions) § Regional Lymph Node Dissections
® Treatment § Individualized therapy
§ Achieve oncologic cure, microscopically negative surgical • Breast Exam
margins, curative resection, palliative resection ® Inspection (Symmetry, Color, Contour, Lesions like dimpling and
§ Oncologic resections nipple inversions, Erythema, erosion, edema)
- R0: microscopically negative margins ® Palpation
- R1: microscopically positive margins • Breast biopsy
- R2: grossly positive margins ® Fine needle: cystic lesions
§ Breast: Radical mastectomy, modified radical, breast ® Core needle: solid tumors
conservation
§ Soft tissue sarcoma: amputation, compartmental resection, REVIEW QUESTIONS
wide excision 1. The following describe the roles of a surgeon except?
® Surgical management a. Responsible for initial diagnosis and management of solid tumors
§ Remove primary tumor and regional lymph nodes b. Coordinates the multidisciplinary care
§ Sentinel node: first node to receive drainage from tumor c. Responsible for definitive surgical therapy
- If negative, no axillary dissection d. All choices are roles of a surgeon
§ Isosulfan blue dye and Tc labelled sulfur colloid or albumin: to 2. This gene is a transcription factor for cycle arrest and apoptosis in
identify sentinel node DNA damage
® Surgery not indicated for metastatic disease a. RB1
• Other modes of treatment b. P53
® Chemotherapy: decrease systemic recurrence and tumor burden c. BRCA1
§ Target specific areas of cell cycle d. APC
® Alkylating agents: Direct damage to DNA
® Antitumor antibiotics: Interfere with DNA and RNA synthesis 3. The following are correctly matched to their MOA except?
a. Antitumor: Interfere with DNA and RNA synthesis
® Antimetabolites: Substitute purine and pyrimidine analogs during
b. Plant Alkaloids: Interfere with tubulin polymerization during the S
S-Phase
phase
® Plant alkaloids: Interfere with tubulin polymerization during M-
c. Antimetabolites: Substitute purine and pyrimidine analogs during
phase
the S phase
® Methods of giving chemotherapy d. Alkylating agents: direct damage to DNA
§ Primary
§ Adjuvant: in addition to current treatment 4. Post-operative disadvantages of radiation therapy include the
§ Neoadjuvant: pre-operative or induction chemotherapy following except?
a. Less radiosensitivity due to hypoxia
Oncology 13.12: SURGICAL ONCOLOGY AND BREAST BIOPS 11 of 12
 b. Post-op adhesions expose more bowels to radiation d. None
c. Large radiation dose due to surgery contamination
d. Inadequate histologic evaluation Answers: 1D, 2B, 3B, 4D, 5D

REFERENCES
5. Which oncologic resection type is correctly matched? (1) ASMPH Batch 2021. 2019. Surgical Oncology and Breast Biopsy.
a. R1: grossly positive margins
b. R2: grossly negative margins
c. R0: microscopally positive margins

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