Tumor growth and spread

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• Section 4
• Tumor growth and spread

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• 1. Biology of tumor growth
• The natural history of malignant tumors can be
  divided into four phase
• A. Transformation
• B. Growth of transformation cells
• C. Local invasion
• D. Distant metastases

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• (1) Kinetics of tumor cell growth
• The rate of tumor growth depends on the
  doubling time of tumor cells, the growth fraction
  of tumor cells, and the loss of tumor cells in
  the growing lesion.
• ? Doubling time of tumor cells
• Total cell cycle time for many tumors is equal
  or even longer then that of corresponding normal
  cells.

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• ? Growth fraction
• The proportion of the proliferative pool
  within the tumor cell population.
• Even in some rapidly growing tumors, the
  growth fraction is merely approximate 20.
• ? The degree of imbalance between cell production
  and cell loss

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• (2) Tumor angiogenesis
• Factors other than cell kinetics modify the
  rate of tumor growth. Most important among these
  is blood supply.
• Angiogenesis is requisite not only for
  contimled tumor growth, but also for metastasis.
• Angiogenesis is necessary for biologic
  correlate of malignancy.

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• Tumor associated angiogenic factors may be
  produced by tumor cells or inflammatory cells
  (macrophages) that infiltrate tumors.
• e. g. vascular endothelial growth factor
  (VEGF) basic fibroblast growth factor (BFGF)

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• (3) Tumor progression and heterogeneity
• ? Tumor progression
• Many tumors become more aggressive and acquire
  greater malignant potential over a period of
  time.

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• ? Tumor heterogeneity
• Despite most malignant tumors are monoclonal
  in origin, by the time they become clinically
  evident, their constituent cells are extremely
  heterogeneous resulting from multiple mutations
  that accumulate independently in different cells.
  Thus the generating subclones are with different
  characteristics. A growing tumor there for tends
  to be enriched for those subclones that are adept
  for survival, growth, invasion, and metastases.

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• 2. Tumor growth
• (1) Rate of growth
• Benign slowly years to decades
• Malignant rapidly moths to years

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• (2) Pattern of growth
• ? Expansile
• a. Well-demarcated and encapsulated
• b. Gradually
• c. Surgically enucleated easely.
• d. The particular growth pattern of benign
  tumors

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Expansile Growth pattern(offered by Song W.Wong)
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• ? Invasive
• a. Progressive infiltration, invasion, and
  destruction of the surrounding tissue
• b. Ill-defined and non-encapsuled
• c. The particular growth pattern of malignant
  tumors
• d. Be surgically enucleated difficultly

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Invasive growth pattern
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• e. The steps and mechanism of invasion
• i. Cancerous cells attaching basement
  membrane
• Cancerous cells have more receptors of lamina
  and fibronectin
• ii. Local proteolysis
• iii. Locomotion

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• ? Exospheric
• a. Tumors growth projecting on the surface,
  booty cavities, or the lumen
• b. Commonly polyp, mushroom, and finger-like
• c. Growth pattern of both benign and
  malignant tumors

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Exospheric growth pattern
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• 3. Tumor spread
• The spread is a cheracteristic of malignant
  tumors
• (1) Local invasion
• Malignant tumor cells invade, penetrate local
  tissue fissure progressively.

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• (2) Metastasis
• Definition metastasis connotes the
  development of secondary implants discontinuous
  with the primary tumor, possibly in remote
  tissue.

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• ? Lymphatic metastasis
• a. This is the most common pathway for
  initial dissemination of carcinoma.
• b. Tumor cells gain access to an afferent
  lymphatic channel and carried to the regional
  lymph nodes.
• In lymph nodes, initially tumor cell are
  confined to the subcapsular sinus with the time,
  the architecture of the nodes may be entirely
  destroyed and replaced by tumor.

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• c. Through the efferent lymphatic channels
  tumor may still be carried to distanced lymph
  rode, and enter the bloodstream by the way of the
  thoracic duct finally.
• d. Destruction of the capsule or infiltration
  to neighboring lymph nodes eventually causes
  these nodes to become firm, enlarged and matted
  together.

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Lymphatic metastasis
Quoted from Prof.Li Yu-Lin Pathology
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• Lymphatic metastasis

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• ? Hematogenous metastasis
• a. This pathway is typical of sarcoma but is
  also used by carcinoma
• b. Process tumor cells ?small blood vessels?
  tumor emboli? distant parts? adheres to the
  endothelium of the vessel? invasive the wall of
  the vessel? proliferate in the adjacent tissue?
  establish a new metastatic tumor.

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• c. follow the direction of blood flow. Tumors
  entering the superior or inferior vena cava will
  be carried to the lungs tumors entering the
  portal system will metastasize to the liver.
• d. Some cancers have preferential sites for
  metastases lung cancer offal metastasize to the
  brain, bones, and adrenal glands.
• Prostate cancer frequently metastasize to the
  bones.
• e. Morphologic features of metastasis tumors
  multiple, circle, scatter

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Blood metastasis
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• ? Implantation metastasis
• a. Tumor cells seed the surface of body
  cavities
• b. Most often involved is the peritoneal
  cavity
• c. But also may affect pleural, pericardial,
  subarachnoid, and joint space.

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• Mechanisms of invasion and metastasis
• ? Invasion of the extracellular metastasis
• a. Loosening up of tumor cells from each other
  E-adhering expression is reduced
• b. Attachment to matrix components cancer cells
  have many more receptors of lamina and
  fibronectin.
• c. Degradation of extra cellular matrix
• Tumor cells can secrete proteolytic enzymes or
  induce host cells to elaborate proteases.

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• ? Vascular dissemination and homing of tumor
  cells
• a. Tumor cells may also express adhesion
  molecules whose ligands are expressed
  preferentially on the endothelial cells of target
  organ.
• b. Some target organs may liberate
  chmoattractonts that tend to recruit tumor cells
  to the site. e. g. insulin-like growth factor ?,
  ?.
• c. In some cases, the target tissue may be not
  an permissive environment. i. g. inhibitors of
  proteases could prevent the establishment of mend
  of a tumor cottony.

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• ? Molecular genetics of metastases
• At present, no single metastasis gene has
  been found, just son conciliates
• a. High expression of nm23 gene often
  accompanied with low metastatic potential.
• b. KAI-I gene, located on 11pn-2, expressed in
  normal prostate but not in metastasis prostate
  cancer.
• c. KISS gene, also located on human chromosome
  ?, analogous manner in human malignant melanoma.

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(Quoted from Robbins Pathology Basis of disease)
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• 4. Tumor recurrence
• Cause
• (1) Tumor cell remnant
• (2) Reclusive metastasis

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• 5. Grading and staging of tumor
• (1) The grading of a cancer attempts to establish
  some estimate of its aggressiveness or level of
  malignancy based on the differentiation of tumor
  cells and number of mitoses within the tumor.
• Grade ? well differentiation, low malignancy
• Grade ? middle differentiation, middle
  malignancy
• Grade ? poor differentiation, nigh malignancy

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• (2) The staging of cancers is based on the size
  of the primary lesion, its extent of spread to
  regional lymph Medes, and metastases.
• Widely used is a so-called TNM system.
• T primary tumor
• N regional lymph node involvement
• M metastases

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• A specific tumor would be characterized as T1,
  T2, T3, or T4, with increasing size of primary
  lesion
• No, N1, N2, N3 to indicate progressively
  advancing nodal disease
• Mo or M, according to whether there are distant
  metastases.