Lecture 37 - Neoplasia Iii
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Neoplasia By Prof. J.T. Anim Department of Pathology Faculty of Medicine
Lecture III
Topics
Tumour invasion
Lymphatic spread Haematogenous spread Transcoelomic spread
Metastasis Staging of malignant neoplasms
Tumour Invasion
Most carcinomas begin as localised growths confined to the epithelium in which they arise If they do not penetrate the basement membrane – carcinoma in situ Malignant tumours grow within the tissue of origin and enlarge and infiltrate normal structures. May extend directly beyond the confines of the organ to involve adjacent tissues.
Tumour Invasion
Acquisition of adequate blood supply – angiogenesis
Derived from venules and capillaries Stimulated by: basic FGF, TGF-α, angiogenin (?TNF-α) Inhibited by: TGF-β1
Endothelial cells degrade their own BM (proteolysis) Migrate into/through EV stroma (motility) Form capillary sprouts (proliferation) Undergo canalisation (proteolysis)
Tumour Invasion
Decreased adhesion of tumour cells to each other (loss of homotypic cell adhesion)
Cell contact units eg, desmosomes, are lost in malignant cells Increased negatively charged repellent molecules on malignant cell surface Cell adhesion molecules, especially Ecadherins:
↑ e-cadherin = ↓ invasiveness (better differentiation) Antibodies to e-cadherin = ↑ invasiveness
Homotypic cell adhesion
Tumour Invasion
Adhesion of malignant cells to BM and interstitial stromal matrices
Must cross tissue barriers eg. BM In situ carcinoma = no breach of BM Invasive carcinoma
Attachment of tumour cells to BM components Lysis of BM matrix Movement of cell through breach in BM
Attachment of tumour cell to BM and EC matrix components via integrins (receptors)
Tumour cells release protease enzymes to dissolve matrix → cell movement Metalloproteinases (collagenases, gelatinases, stromelysins), heparanases, serine dependent proteases, thiol dependent proteases, others (plasminogen activator from tumour cells)
Active movement of malignant cells Invasion and metastasis requires active movement of the tumour cell Both random (kinesis) and directed (taxis) Promoted by intact and fragmented EC matrix molecules
Motility is regulated by: 2. Tumour autocrine motility factor (AMF) 3. Scatter factor (secreted by fibroblasts) - paracrine
Tumour Invasion
Invading cells follow path of least resistance
Natural clefts within tissue planes eg. invasion of muscle coat of GIT.
Other changes associated with neoplasia in EC matrix
Destruction of matrix of tumour cells Increased production of matrix by the host (desmoplasia) Synthesis of matrix by tumour cells
Neoplasia - Invasion The undifferentiated cells lose cohesiveness and acquire the ability to invade neighbouring tissues and blood vessels leading to dissemination
Adenocarcinoma of the Colon invading the musularis propria
Lymphatic Spread
BM of lymphatics do not contain type IV collagen or laminin In experimental models:
Cells line up alongside lymphatic channel Enter lymphatics by:
Pushing cytoplasmic processes between endothelial cells Travelling through inter-endothelial gaps
Grow along lumen as continuous cords (extend widely) Spread to regional nodes eg. breast carcinoma Lymphatic blockage
Diversion of flow +/- tumour cells to satellite nodules Lymphoedema of tissues caudal to block
Lymphatic Spread
Tumour cells in lymph node
Subcapsular sinus → central sinuses Tumour cells
Destroyed Remain dormant for a long period Establish a growing focus → replace LN
Access to blood stream
Invasion of small intranodal blood vessels Invasion of extranodal vessels via breached capsule Opening of small lymphatico-venous communications Via thoracic duct
Lymph Node: - Most tumours especially carcinomas
Metastatic deposits in paraaortic lymph nodes
Blood Spread
Direct entry into bloodstream by:
Invading small new vessels within the tumour Invading host blood vessels near growing edge of tumour
Sarcomas often contain large vascular channels partly lined by malignant cells which may be shed directly into blood stream Permeation in continuity along invaded venous channels (renal ca, hepatocellular ca, bronchial ca.) Tumour cells form solid mass along vein → IVC → right atrium
Metastasis
Def:
Malignant cells established at a point distant from the original primary lesion, with no continuity between them
Mechanisms
Secondary to lymphatic invasion Secondary to blood vessel invasion “seeding out” across serosa-lined spaces
Metastasis
It is basically an embolic process involving:
Liberation of cells from primary tumour mass Invasion of blood vessels or lymphatics Transfer of tumour cells as emboli Adhesion of tumour cells to endothelium on vascular bed Migration from vessels after impaction Survival at the new site ( requires angiogenesis) Multiplication and growth to form secondary tumours.
Processes in tumour metastasis
Lung: - Breast, stomach, sarcomas
Metastasis
Heterogeneity of malignant cells
Only a small fraction of tumour cells survive to form secondaries Some primary tumours metastasise to preferred sites (homing)
Breast cancer – lung, liver, bone, brain Lung cancer – brain, adrenals Prostate cancer - bone
Homing mechanism is unknown
May be due to surface membrane of malignant cell Specific patterns of surface proteins for certain tumours
Liver: GI, pancreatic (portal venous drainage) Lung, breast, GU, malignant melanoma,
Metastatic deposits in the Liver
Brain Lung, malignant melanoma
Common Patterns of Metastasis
Skeleton
Lung breast, prostate, kidney, thyroid
Production of new bone (osteoblastic) Destruction of bone (osteolytic)
Adrenal (most frequently involved endocrine organ)
Lung, breast, kidney
Metastatic deposits in bone
Transcoelomic spread
Follows invasion of serosal lining Local inflammatory response to infiltrating tumour cells Malignant cells incorporated into inflammatory exudate Small groups of cells detached and swept away by fluid portion of exudate into serosal cavity Settle on walls of serosal cavity Some proliferate into secondary deposits Elicit more exudation → fluid accumulation in cavity
Pleura: -
Transcoelomic Spread
Peritoneal cavity Gastric, colonic, ovarian cancer
Gravitational seedings Deposits in pouch of Douglas Involvement of ovaries Enlarged ovaries with smooth capsule + stromal desmoplastic reaction = Kruckenberg tumour
Peritoneum: - Most intra-abdominal tumours
Metastasis
Genetic control of metastasis
Suppressor gene for metastasis (NM23) on long arm of chromosome 17 Human breast cancer shows poor survival with loss of expression of NM23 Mutation/abnormal expression of oncogenes (ras, myc) associated with aggressive behaviour of tumours
Summary of mechanisms in tumour spread and metastasis
Spread & Metastasis
Extent of spread = staging
Staging is important in determining prognosis eg. Dukes’ staging of colonic/rectal carcinoma
TNM Staging of Malignant Tumours
TNM Staging of Malignant Neoplasms
Lecture III
Topics
Tumour invasion
Lymphatic spread Haematogenous spread Transcoelomic spread
Metastasis Staging of malignant neoplasms
Tumour Invasion
Most carcinomas begin as localised growths confined to the epithelium in which they arise If they do not penetrate the basement membrane – carcinoma in situ Malignant tumours grow within the tissue of origin and enlarge and infiltrate normal structures. May extend directly beyond the confines of the organ to involve adjacent tissues.
Tumour Invasion
Acquisition of adequate blood supply – angiogenesis
Derived from venules and capillaries Stimulated by: basic FGF, TGF-α, angiogenin (?TNF-α) Inhibited by: TGF-β1
Endothelial cells degrade their own BM (proteolysis) Migrate into/through EV stroma (motility) Form capillary sprouts (proliferation) Undergo canalisation (proteolysis)
Tumour Invasion
Decreased adhesion of tumour cells to each other (loss of homotypic cell adhesion)
Cell contact units eg, desmosomes, are lost in malignant cells Increased negatively charged repellent molecules on malignant cell surface Cell adhesion molecules, especially Ecadherins:
↑ e-cadherin = ↓ invasiveness (better differentiation) Antibodies to e-cadherin = ↑ invasiveness
Homotypic cell adhesion
Tumour Invasion
Adhesion of malignant cells to BM and interstitial stromal matrices
Must cross tissue barriers eg. BM In situ carcinoma = no breach of BM Invasive carcinoma
Attachment of tumour cells to BM components Lysis of BM matrix Movement of cell through breach in BM
Attachment of tumour cell to BM and EC matrix components via integrins (receptors)
Tumour cells release protease enzymes to dissolve matrix → cell movement Metalloproteinases (collagenases, gelatinases, stromelysins), heparanases, serine dependent proteases, thiol dependent proteases, others (plasminogen activator from tumour cells)
Active movement of malignant cells Invasion and metastasis requires active movement of the tumour cell Both random (kinesis) and directed (taxis) Promoted by intact and fragmented EC matrix molecules
Motility is regulated by: 2. Tumour autocrine motility factor (AMF) 3. Scatter factor (secreted by fibroblasts) - paracrine
Tumour Invasion
Invading cells follow path of least resistance
Natural clefts within tissue planes eg. invasion of muscle coat of GIT.
Other changes associated with neoplasia in EC matrix
Destruction of matrix of tumour cells Increased production of matrix by the host (desmoplasia) Synthesis of matrix by tumour cells
Neoplasia - Invasion The undifferentiated cells lose cohesiveness and acquire the ability to invade neighbouring tissues and blood vessels leading to dissemination
Adenocarcinoma of the Colon invading the musularis propria
Lymphatic Spread
BM of lymphatics do not contain type IV collagen or laminin In experimental models:
Cells line up alongside lymphatic channel Enter lymphatics by:
Pushing cytoplasmic processes between endothelial cells Travelling through inter-endothelial gaps
Grow along lumen as continuous cords (extend widely) Spread to regional nodes eg. breast carcinoma Lymphatic blockage
Diversion of flow +/- tumour cells to satellite nodules Lymphoedema of tissues caudal to block
Lymphatic Spread
Tumour cells in lymph node
Subcapsular sinus → central sinuses Tumour cells
Destroyed Remain dormant for a long period Establish a growing focus → replace LN
Access to blood stream
Invasion of small intranodal blood vessels Invasion of extranodal vessels via breached capsule Opening of small lymphatico-venous communications Via thoracic duct
Lymph Node: - Most tumours especially carcinomas
Metastatic deposits in paraaortic lymph nodes
Blood Spread
Direct entry into bloodstream by:
Invading small new vessels within the tumour Invading host blood vessels near growing edge of tumour
Sarcomas often contain large vascular channels partly lined by malignant cells which may be shed directly into blood stream Permeation in continuity along invaded venous channels (renal ca, hepatocellular ca, bronchial ca.) Tumour cells form solid mass along vein → IVC → right atrium
Metastasis
Def:
Malignant cells established at a point distant from the original primary lesion, with no continuity between them
Mechanisms
Secondary to lymphatic invasion Secondary to blood vessel invasion “seeding out” across serosa-lined spaces
Metastasis
It is basically an embolic process involving:
Liberation of cells from primary tumour mass Invasion of blood vessels or lymphatics Transfer of tumour cells as emboli Adhesion of tumour cells to endothelium on vascular bed Migration from vessels after impaction Survival at the new site ( requires angiogenesis) Multiplication and growth to form secondary tumours.
Processes in tumour metastasis
Lung: - Breast, stomach, sarcomas
Metastasis
Heterogeneity of malignant cells
Only a small fraction of tumour cells survive to form secondaries Some primary tumours metastasise to preferred sites (homing)
Breast cancer – lung, liver, bone, brain Lung cancer – brain, adrenals Prostate cancer - bone
Homing mechanism is unknown
May be due to surface membrane of malignant cell Specific patterns of surface proteins for certain tumours
Liver: GI, pancreatic (portal venous drainage) Lung, breast, GU, malignant melanoma,
Metastatic deposits in the Liver
Brain Lung, malignant melanoma
Common Patterns of Metastasis
Skeleton
Lung breast, prostate, kidney, thyroid
Production of new bone (osteoblastic) Destruction of bone (osteolytic)
Adrenal (most frequently involved endocrine organ)
Lung, breast, kidney
Metastatic deposits in bone
Transcoelomic spread
Follows invasion of serosal lining Local inflammatory response to infiltrating tumour cells Malignant cells incorporated into inflammatory exudate Small groups of cells detached and swept away by fluid portion of exudate into serosal cavity Settle on walls of serosal cavity Some proliferate into secondary deposits Elicit more exudation → fluid accumulation in cavity
Pleura: -
Transcoelomic Spread
Peritoneal cavity Gastric, colonic, ovarian cancer
Gravitational seedings Deposits in pouch of Douglas Involvement of ovaries Enlarged ovaries with smooth capsule + stromal desmoplastic reaction = Kruckenberg tumour
Peritoneum: - Most intra-abdominal tumours
Metastasis
Genetic control of metastasis
Suppressor gene for metastasis (NM23) on long arm of chromosome 17 Human breast cancer shows poor survival with loss of expression of NM23 Mutation/abnormal expression of oncogenes (ras, myc) associated with aggressive behaviour of tumours
Summary of mechanisms in tumour spread and metastasis
Spread & Metastasis
Extent of spread = staging
Staging is important in determining prognosis eg. Dukes’ staging of colonic/rectal carcinoma
TNM Staging of Malignant Tumours
TNM Staging of Malignant Neoplasms
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