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									                                                                                   MOD #129
                                                                          Thur, 05/22/03, 9am
                                                                                   Dr. Vuitch
                                                                                  Paul Duong
                                                                                Page 1 of 8
                               CLINICAL INTEGRATION

I. Characteristics of benign and malignant neoplasm
 These are general principles of classification of neoplasm. There’s always exception
   to the classification.
 The test and the quizzes will be based on these general principles.
 Next year, we’ll be learning different neoplasm types.
    A. Benign neoplasm characteristics
              a) The cells are well well-differentiated
              b) They tend to resemble the normal tissue histologically and functionally.
              c) Example: the thyroid follicular cells will resemble normal cells:
                               (1) They do take up iodine
                               (2) And produce hormones.
         2. Usually little atypia: only mild pleomorphism
         3. Slow growth: steadily and predictable pattern
         4. Circumscribed or encapsulated:
              a) without invasive growth
              b) Capsule: the responding of the tissue of the host to the expansion of the
                   benign neoplasm. Such that fibroblast lay down collagen and make
                   pseudocapsule (correct term: not make by the neoplasm itself).
         5. Non-invasive:
         6. Do not metastasize:
              a) The most important characteristic that differentiate benign from
              b) Only malignancy can metastasize. The next best criteria to indicate
                   malignancy is invasive growth.
    B. Malignant neoplasm characteristics
         1. Some degree of lack of differentiation:
              a) Both morphologically and functionally compared to the normal cells.
              b) The degree of the differentiation from the normal cells will tell us if the
                   cells are:
                               (1) Well differentiated
                               (2) Moderately differentiated
                               (3) Poorly differentiated.
              c) For instances: thyroid cells will look different than normal and secrete
                   more hormones due to lack of normal control: homeostasis like normal
                   tissues have.
         2. Anaplasia and dysplasia in malignant neoplasm which include:
              a) Pleomorphism:
                               (1) Variation from cells to cells in appearance.
                               (2) abnormal mitotic figures: characteristic of anaplasia:
                               tumor giant cells
              b) Hyperchromasia of the chromatin of the nucleus
              c) Increase in N: C ratio
                                                                                  MOD #129
                                                                         Thur, 05/22/03, 9am
                                                                                  Dr. Vuitch
                                                                                 Paul Duong
                                                                                Page 2 of 8
         3.   Rapid growth; mitoses (often atypical):
              a) Neoplasm have higher mitotic rate than benign.
              b) Have variable growth:
                              (1) Sometime have dormant period followed by explosive
                              growth. Eg, pt with breast cancer. It’s normal to see pt w
                              breast cancer seemed to be treated or cured but 5 to 10 yrs.
                              later suddenly metastatic disease blossom.
                              (2) Also have necrosis: so the number of cell proliferate
                              and the number of cells undergo necrosis may vary. You
                              may even have shrinking of the tumor due to increase
         4.   Locally invasive:
         5.   Metastatic capability:
              a) The hallmark of malignancy
              b) However, not all malignancy will metastasize

This figure represents benign and malignant neoplasm. The benign on the left and the
malignant is on the right. And the neoplasm follows the general characteristics described
One general rule that is broken with regularity by neoplasm:
    Sarcoma tends to metastasize hematogenously.
    Carcinoma tends to metastasize first via the lymphatic channel to regional lymph
    This is not always true since some tumors may break the rule.
    C. Metastasis: the most important marker of malignancy.
         1. Metastasis –
              a) neoplastic cell implants discontinuous from primary malignancy;
                  unequivocal marker
              b) However, there are some confusing issues: eg, pt is a cigarette
                  smoker the entire bronchial tree will be exposed to the carcinogenic
                  agent so it’ll be possible that one would develop cancer in the left
                  lung and one in the right lung. Those are two discrete primary
                  carcinoma. One is not metastasis of the other.
                                                                              MOD #129
                                                                     Thur, 05/22/03, 9am
                                                                              Dr. Vuitch
                                                                             Paul Duong
                                                                            Page 3 of 8
         c) So you have implants that are discontinuous but separate tumors. This
            phenomenon is called field effect or field defect causes the whole
            bronchial tree exposed to the same carcinogenic agent.
       d) Genetic defect, for eg, the condition called familial polyposis coli. This
            is a hereditary defect in one gene that causes adenoma ( benign) of the
            colon. Only one hit in the chromosome and these pts will develop
            hundreds of adenoma in the colon.
       e) And invariably one of those adenomas will become adenocarcinoma in
            the colon. It’s not uncommon for these pts have synchronous or
            dyssynchronous adenocarcinoma after the first one.
       f) The correct therapy is to remove the colon to remove all the tissues at
       g) The main concept is that the multifocal diseases are not the same as
            metastatic disease. There are some markers particularly using X
            chromosome to tell if the to mass are clonal or different clone as in
            multifocal diseases.
       h) The general rule, if you got one big mass in the lung and you got a
            small mass in the nearby lymph node then it is a primary tumor and its
   2. 30% of newly diagnosed patients with solid tumors will have metastatic
       diseases already.
   3. The two paragraph below are contradict:
   4. “In general, the more aggressive, the more rapidly growing, and the larger
       the primary neoplasm, the greater the likelihood that it will metastasize or
       already has metastasized.”
   5. This statement is wrong: “No judgment can be made about the probability
       of metastasis from pathologic examination of the primary tumor.” What it
       means is that in an individual pt, by examine the primary neoplasm you
       can’t predict the likelihood for that individual pt to already have metastatic
       disease or to develop metastatic diseases.
D. Pathways of metastatic spread: three main pathways:
   1. Seeding of body cavities and surfaces -
       a) The most common site is the peritoneal cavity, the pleural cavity.
       b) Eg, the malignancy of the colon perforated through the wall of the
            colon or the ovarian malignancy through the surface of the ovary and
            then the cells shed into the peritoneal fluid.
       c) Usually they will cause incr secretion of the fluid then you will develop
            ascites with malignant cells floating in it and deposit somewhere in the
            peritoneal cavity and start to grow.
       d) Often with floating malignant cells in effusion
   2. Lymphatic spread - natural drainage route to regional lymph nodes,
       a) For eg, the first site of the lateral breast drainage will go to the axilla.
            The medial site of the breast will go to the mediastinal chains.
       b) So for the pts with breast cancers there are two poss sites for where the
            first regional lymph node may be. It can be lateral or medial.
                                                                                MOD #129
                                                                       Thur, 05/22/03, 9am
                                                                                Dr. Vuitch
                                                                               Paul Duong
                                                                              Page 4 of 8
          c)   If the neoplasm is big enough both the lateral and medial will be
          d) We know where the lymph node drainage will go.
          e) For eg, melanoma of the belly button lymphatic will go to the either
               groins or either axillas. Or may go to all four regions.
          f) We can be able to inject dyes to see where the lymph drained. Or you
               can use radioisotope tracing to access areas at risk for metastasize.
          g) Sometime the malignant cells can go the lymph node and proliferate
               and cause incr size. However you must differentiate with reactive
               hyperplastic lymph nodes due to infection and other causes by biopsy.
               Don’t jump to the conclusion that the enlargement of the lymph node is
               due to metastasize.
     3.   Hematogenous spread - usually vein invasion, rarely to arteries because
          arteries have a lot of elastic, thick muscle walls.
          a) If metastasize go to the vena cavae, metastasize will most likely go the
               lungs instead of stopping at the right heart (unfavorable environment).
          b) Follows blood flow; liver and lungs most often secondarily involved
          c) Most of the malignancy in the liver are metastasize, primary
               malignancy of the liver is very uncommon.

   This first slide shows pic of the lymph node. The blue spots are the lymphocytes.
    This also shows the capsule and the sub capsule, the sinus. The larger cells are
    malignant cells. First it will involve the subcapsular lymph node, and then as the
    tumor growth it will involve the parenchymal of the lymph node.
   The second pic is the lymph node metastasis. This is the section of the liver which
    shows many tumor nodules. The general principle: if the organ presents with
    multiple nodules then it may be metastasize neoplasm rather than primary
    neoplasm. This common pic of the liver you may see in pts with colon cancer,
    stomach cancer …any primary malignancy within the peritoneal cavity.
                                                                              MOD #129
                                                                     Thur, 05/22/03, 9am
                                                                              Dr. Vuitch
                                                                             Paul Duong
                                                                           Page 5 of 8

     There are residual hepatocytes cords on the periphery. And the large glands are
      metastasis adenocarcinoma secrete mucins into the lumen.
II. Epidemiology
    A. Cancer incidence:
        1. 1998 - 1.2 million new cancer cases ( doesn’t include plus 1 million more
           skin cancers and about 100,000 in situ cancers- noninvasive cancers that
           has not reach the basement membrane)
           a) 565,000 deaths; 23% of US mortality
        2. Sir Percival Pott - Scrotal cancer in chimney sweeps may be due to hygiene
        3. Other causes (epidemiologic perspective): environmental, racial (genetic),
    B. Cancer Incidence and Death US, 1998
        1. Women        Incidence Death
           a) Melanoma 2.8              1
           b) Lung                  13.3      24.7
           c) Pancreas        2.4       5.5
           d) Colon                 11.1      10.5
           e) Urinary         4.6       3.2
           f) WBC                     6.7       8.2
           g) Breast                29.7      16
           h) Ovary                   4.2       5.3
           i) Uterus                  8.2       4.1
            Summary:
            Breast cancer is the most common malignant cancer that the women get.
               However, it’s not the most common cause of death in the US. Only ½
               pts having the cancer die.
            Lung cancer is only half as frequent in women as breast cancer but
               responsible for a higher percent of death in women.
            Colon cancer is also a common cancer as well and has about the same
               percentage of death
            So lung cancer is the most aggressive, then colon, and breast cancer.
        2. Men           Incidence Death
           a) Melanoma 3.8             1.5
                                                                            MOD #129
                                                                   Thur, 05/22/03, 9am
                                                                            Dr. Vuitch
                                                                           Paul Duong
                                                                         Page 6 of 8
         b)    Lung               14.5      31.6
         c)    Pancreas     2.2      4.7
         d)    Colon              10.2       9.5
         e)    Urinary      9.3      5.3
         f)    WBC                  8.1      8.7
         g)    Prostate    29.3     13.3
             Lung cancer seems to be similar frequency in both men and women.
              There’s a higher death rate in men.
             Colon cancer seems to be the same in both grp.
             Breast and prostate are very similar statistically.
             However, prostate and breast still be the second most common killer of
              men and women respectively.

  Three cancers down on the first graph:
      o Stomach cancer most like due to better preservation of food.
      o Uterine ( mostly cervical) due to advance screening: Pap smear.
      o Colon and rectum cancer
 However, lung cancer seem to incr
 In men, second graph:
      o Lung cancer tremendously incr
 C. geographic and environmental factors
    1. Remarkable differences can be found in the incidence and death rates of
        specific forms of cancer around the world, in specific ethnic groups, in
        certain occupational exposures.
    2. Relationship of certain cancers of Japanese immigrants vs. California
        whites, reported 1975
                                                                         MOD #129
                                                                Thur, 05/22/03, 9am
                                                                         Dr. Vuitch
                                                                        Paul Duong
                                                                      Page 7 of 8

        a)  Pple in japan have a high rate of stomach cancer: 6 times that of
            California whites. But low rate of colon and prostate cancers.
       b) Immigrated Japanese have lower risk on liver and stomach cancer but
            incr risk of colon and prostate cancer.
       c) The second generation Japanese has the same risk of colon and prostate
            cancers as the California whites.
       d) In conclusions, stomach cancer may be due to carcinogen in the diet.
            And the Japanese diet seems to be heavy in certain pickles food: high
            seafood content.
       e) Liver cancer to a great extent due to hepatitis B exposure.
       f) Colon cancer may be due to hereditary and high fat content in the diet.
       g) Prostate cancer we don’t know but may be due to high fat content in the
            diet (Mc Donald).
   3. “Cigarette smoking has been called the single most important
       environmental factor contributing to premature death in the U.S.”
   4. cigarette smoking: cancers associated with smoking
       a) oral (mouth, pharynx, larynx)
       b) esophagus: also more risk if also a heavy drinker
       c) pancreas: don’t know
       d) Bladder: presumably the carcinogen excreted in the urine.
       e) Cervical: smoking pts predispose to human papilloma virus
       f) Lung:
       g) Most pple who smoke do not develop cancers
       h) and we are not discussing atherosclerosis, peripheral vascular disease,
            cerebrovascular disease, Raynaud syndrome, Buerger’s dz, others
D. Age and cancer
   1. Different age grps have different incidences of different kind of cancers.
   2. Most occur after age 55, but each age group has its own predilection(s) for
       certain cancers
   3. Under age 15 - Leukemia/lymphoma, brain, endocrine, soft tissue sarcoma
       (<1% of total). These are uncommon in adult population.
   4. Over age 55 - Lung, colon/rectum, prostate, breast, pancreas (85% of total)
                                                                              MOD #129
                                                                     Thur, 05/22/03, 9am
                                                                              Dr. Vuitch
                                                                             Paul Duong
                                                                            Page 8 of 8
E. Heredity and cancer, Table 8-6:3 main categories
   1. Inherited cancer syndromes (autosomal dominant) –
       a) Retinoblastoma, familial colon polyposis, MEN, neurofibromatosis,
            von Hippel-Lindau.
       b) All cells in the body have one hit in one chromosome. For instance, in
            developing the retina, billions of cells are required. If one cell has the
            second hit on the same gene then the Rb gene is inactivated and no
            longer suppress cell proliferation retinoblastoma cancer frequently
            both eyes are affected.
   2. Familial cancers –
       a) Earlier age at onset, multiple or bilateral neoplasms, uncertain genetics
            in most. Eg, breast cancer
   3. Autosomal recessive syndromes of defective DNA repair (xeroderma
       pigmentosa): faulty repair of radiation DNA skin cancer.
   4. Acquired pre-neoplastic disorders (leukoplakia, solar keratosis, atrophic
       gastritis, ulcerative colitis). Majority of these pts won’t develop cancer.

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