Surgery I 3.4 Surgical Oncology - Dr. Hipolito

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Surgical Oncology

Text of Surgery I 3.4 Surgical Oncology - Dr. Hipolito

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    Atienza, Austria, Balbin (09272265029), Bandoma, Baez, Banico

    Dr. Hipolito | March 6, 2014

    SURGERY 3.4 Principles of Surgical Oncology 2013-2014 2nd

    OUTLINE I. Carcinogenesis VI. Postoperative Management II. Cancer Metastasis VII. Principles of Chemotherapy III. Preoperative Planning VIII. Cancer Treatment Strategies IV. Intraoperative Conduct IX. Principles of Radiation Therapy of Operation V. Types of Cancer Operations X. On-going Trials in Cancer Therapy References: Powerpoint, recording

    I. CARCINOGENESIS Single cell (clonogenic origin) undergoes complex molecular

    and biochemical interactions resulting in malignant transformation. This means, a normal cell acquires potential to grow and replicate due to several factors (smoking, drinking, genetics/hereditary). Environmental and hereditary factors cause underexpression or overexpression of genes. Balance between the tumor suppressor genes and thos genes which causes cancer, oncogenes.

    Interaction of cancer promoting genes (oncogenes) and cancer protecting genes (suppressor genes) o Overexpression of oncogenes + the effects of

    environmental factors o Deletion/underexpression of suppressor genes (ex. P53)

    Figure 1. Loss of normal growth control

    HALLMARKS OF CANCER o Sustained proliferative signaling (growth factors-tyrosine

    kinase) o Evades growth suppressors (Rb and TP53) o Resist cell death (loss of Apoptotic potential) o Replicative immortality (expression of Telomerase)

    Telomerase, the specialized DNA polymerase that adds telo- mere repeat segments to the ends of telomeric DNA

    o Induces angiogenesis (VEGF and Thrombospondin)- target these factors to block growth

    o Evades immune response o Creates tumor microenvironment- target not only the

    cancer cells but also the surrounding tissue (Hedgehog Hypothesis)

    o Invasion and Metastasis (MAIN HALLMARK): Loss of contact inhibition

    Normal cell can grow. A benign tumor can grow but it has less or no ability to invade other structure.

    Cancer has propensity to go to other places in the body and grow there and cause invasion. Basically, a cancer is a space occupying lesion. It does not produce any toxin that will kill you. It will just grow and invade leading to death.

    Down regulation of E-Cadherin Macrophages (activated by IL4 produced by cancer

    cells) - Macrophages at the tumor periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases (MMP) and cysteine cathepsin proteases

    Figure 2. To illustrate what is meant by normal growth control, consider the skin. The thin outermost layer of normal skin, called the epidermis, is roughly a dozen cells thick. Cells in the bottom row of this layer, called the basal layer, divide just fast enough to replenish cells that are continually being shed from the surface of the skin. Each time one of these basal cells divides, it produces two cells. One remains in the basal layer and retains the capacity to divide.

    The other migrates out of the basal layer and loses the capacity to divide. The number of dividing cells in the basal layer, therefore, stays the same.

    Figure 3. The beginning of Cancerous Growth. Cancer cells replicate until it invade the basement membrane.


    6th LE Schedule

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    SURGERY 3.4

    Figure 4. This gradual increase in the number of dividing cells creates a growing mass of tissue called a "tumor" or "neoplasm". If the rate of cell

    division is relatively rapid, and no "suicide" signals are in place to trigger cell death, the tumor will grow quickly in size; if the cells divide more slowly, tumor growth will be slower. But regardless of the growth rate, tumors

    ultimately increase in size because new cells are being produced in greater numbers than needed. As more and more of these dividing cells accumulate,

    the normal organization of the tissue gradually becomes disrupted.

    Figure 5.Invasion and Metastasis. When cancer cells reach the vascular supply and drainage, they are transported by the circulatory system to

    distant sites

    Figure 6. Distant


    Example: o Thyroid Cancer (Papillary carcinoma of the thyroid) most

    common region of metastasis is the lymph node. Eventually, it will go to the lungs, and then bones

    o Squamous Cell Carcinoma of the skin doesnt readily metastasize

    FACTORS o Oncogenic viruses (ex. HSV/HPV & cerv CA) o Chemicals (ex. Smoking & lung CA) o Chronic irritation (ex. hyperkeratosis & oral cavity cancer) o Genetic factors (ex. BRCA1/BRCA2 & breast CA)

    Note: Interplay of the factors will lead to cancer. Example, if you dont have any gene that predisposes you to lung cancer, even if you smoke everyday, you will not have cancer. But if you have a gene for lung cancer caused by smoking, even one stick of smoke will trigger development of cancer.

    CELL KINETICS this tells the aggressiveness of the tumor, kind of treatment you want to initiate.

    o G0 phase State of cells not in the active cell cycle but capable of entering G1 upon stimulation.

    o Gap 1 phase (G1) period from mitosis to start of DNA synthesis.

    o DNA Synthesis (S) o Gap 2 phase (G2) period between DNA synthesis to next

    mitotic phase. o Mitotic phase (M) cell division seen morphologically.

    A. Cell Cycle

    Figure 7. The

    Cell Cycle. In cancer cells, the stage of terminal differentiation is deleted. Most cancer cells

    undergo G0 phase or the actively replicating phase (2014B trans). Gap 1 phase (G1) Period from mitosis to start of DNA


    DNA synthesis (S)

    Gap 2 phase (G2) period between DNA synthesis to next mitotic phase

    Mitotic phase (M) cell division seen morphologically

    Factors that prevent cells to go into G0 or latent phase (smoking, viruses, chronic irritation, etc)

    Gap 1 phase (G1) Period from mitosis to start of DNA synthesis

    B. Cell kinetic

    Intermitotic Time

    Duration of 1 cell cycle to another cell cycle (ave. 8 24 hrs)

    S phase (ave. 6 10 hrs)

    Cells rapidly proliferating will have shorter intermitotic time

    If a cancer has a very short intermitotic time, you are dealing with a very aggressive cancer; the doubling time decreases

    C. Contents of Cancerous Tissues

    Actively proliferating cells (clonogenic stem cells)

    Non-actively proliferating cells but maintaining clonogenic capacity o Proliferation may have been inhibited by lack of nutrients

    or other homeostatic factors Cells that have lost clonogenic capacity

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    SURGERY 3.4

    Clonogenic stem cells remain latent and thus are hard to treat when given chemotherapy since they are not replicating. Chemotherapy only works on rapidly dividing cells.

    Tumor cells in the periphery where neovascularization is present, are well oxygenated and rapidly dividing o Rapid cell division promote detachment & entry to


    Centrally located cells subject to decrease in PO2 retain clonogenic activity and can metastasize

    Figure 8.Contents of Cancerous Tissue

    Clinical implication

    The best area to biopsy is the periphery, not the center of the tumor.

    o The areas at the periphery are usually the areas most oxygenated and where cells are rapidly dividing. The tissues at the center usually becomes necrotic.

    A tumor on diagnostic imaging that is hypervascular is probably cancerous. o Difficult to penetrate by cytotoxic agents Why?

    Tumor cells in the periphery where neovascularization is present, are well-oxygenated and rapidly dividing. o Rapid cell division promote detachment & entry to lymphatics

    Centrally-located cells subjected to decrease in PO2 retain clonogenic activity and can metastasize

    C. Tumor growth

    Expressed in terms of volume doubling time (DT)

    Range: week to one year with median DT of 60 days Table 1:

    Breast 130 days

    Lungs 160 days

    Melanoma 140 days

    Metastatic Melanoma 64 days

    Situational example: If there is a suspicious lesion in the breast that is not amenable to any kind of biopsy, then the best way to see if there is an increase in size is to do a repeat mammography 3-4 months after the initial testing. Knowledge of the doubling time tells us when to do surveillance.


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    D. Gompertzian Curve

    Figure 9.Gompertzian Curve

    Small tumor close to 100% of cells proliferating

    As tumor enlarges, more cells drop out of proliferating cycle due to the lack of nutritional supply

    Decrease in growth rate with increasing size rather than a linear/exponential growth o Lack of nutrients/blood supply alter growth rate o Large tumors may have many cells in G0 or G1 o Growth altered by immune system

    1.0 cm tumor (clinically detectable) contains 109 cells that are a