Neoplasia II 2024-2025 PDF

Neoplasia II Invasion, Metastasis and Effects of Tumors Session 10 L10 Prof. Dr. Hadeel Abdulelah Karbel Histopathologist F. I. C. M. path. 1 objectives 1) Define invasion and metastasis. 2) Describe the mechanisms facilitating invasi...

Neoplasia II Invasion, Metastasis and Effects of Tumors Session 10 L10 Prof. Dr. Hadeel Abdulelah Karbel Histopathologist F. I. C. M. path. 1 objectives 1) Define invasion and metastasis. 2) Describe the mechanisms facilitating invasion and metastasis 3) Describe the routes and common sites of metastasis. 4) Describe the local effects of benign and malignant neoplasms 5) Describe the systemic effects of neoplasms 6) Explain why Neoplasms kill people 2  WHAT IS INVASION? Ability of cells to break through basement membrane and then spread through the stroma (extra cellular matrix). 1.Into surrounding tissue: Invasive Carcinoma 2.In lymphatic/vascular channels Characteristic of malignant cells 3  Metastasis The spread of a malignant tumour to a distant (i.e. non adjacent) site A metastasis is often referred to as a secondary tumour, with the site of origin being the primary tumour. 4  HOW DO CELLS INVADE AND SPREAD? Complex mechanism involving various factors. 1.Malignant cells do not adhere (stick) to the same extent as normal cells 2.Altered synthesis of enzymes that breakdown basement membrane and stroma 3.Factors produced that help cells become motile (motility factors) Malignant cells show a change in their interaction with the surrounding stroma. 5  1. Altered Cell Adhesion 6  ALTERED CELL ADHESION loosening of tumor cells. CADHERINS are calcium dependent glycoproteins present at cell membrane. They interact homotypically between cells to bind them together Linked to the actin cytoskeleton by catenins. Reduced expression and alterations in interactions in cancer cells, allowing cells to move apart. – Oesophagus, colon, breast, prostate 7 8  Loss of membraneous E cadherin in lobular carcinoma of the breast 9  ALTERED CELL ADHESION INTEGRINS are cell surface glycoproteins composed of two subunits: α+β Many biological functions eg leukocyte adhesion, platelet adhesion 10  ALTERED CELL ADHESION Receptors for different components of the basement membrane eg. Fibronectin,collagen Reduced expression of integrins modifies the contact between the cell and stroma allowing movement. 11  2. ALTERED ENZYME SYNTHESIS AND INTERACTION degradation of the basement membrane and interstitial connective tissue. Different enzymes can modify stroma allowing cells to break through basement membrane and spread eg. Matrix Metalloproteinases: – Zinc dependent enzymes – MMP2 and MMP9 = collagen IV – MMP1 = collagen I Changes in attachment of tumor cells to ECM proteins. 12  3. Motility Cells propelled through the degraded basement membrane and lysed stromal matrix Such movement seems to be potentiated and directed by : – cell derived motility factors – autocrine motility factors – Cleavage products of matrix proteins eg laminin – Other ligands eg Wnt5a in melanoma – Increased expression of receptors for motility factors eg. Met oncogene – HGF receptor 13 14 15  The Importance of ECM The ECM (stroma) is not an inert, passive component of invasion May promote or inhibit invasion Manipulated by malignant cells to aid their passage. – Growth promoting factors – Angiogenic factors – Chemotactic factors 16  Metastasis 17  WHAT IS METASTASIS? Ability of malignant cells to invade into lymphatics, blood vessels and cavities and spread to distant sites. Cells must be able to invade out of channels and grow at distant site. Not all circulating cancer cells will settle at a distant site and be able to grow. 18  The site of extravasation and the organ distribution of metastases generally can be predicted by the location of the primary tumor and its vascular or lymphatic drainage. In many cases, however, the natural pathways of drainage do not readily explain the distribution of metastases. Such organ tropism may be related to the following mechanisms: 1. Expression of adhesion molecules by tumor cells whose ligands are expressed preferentially on the endothelium of target organs 19 Cont… 2. expression of chemokines and their receptors. e. g. Human breast cancer cells express high levels of the chemokine receptors CXCR4 and CCR7. The ligands for these receptors (i.e., chemokines CXCL12 and CCL21) are highly expressed only in those organs to which breast cancer cells metastasize. 3. Once they reach a target, the tumor cells must be able to colonize the site. in some cases, the target tissue may be unfavorable soil for the growth of tumor seedlings. For example, although well vascularized, skeletal muscles are rarely the site of metastases. 20  WHY DON’T ALL MALIGNANT CELLS METASTASISE? Cells may invade and circulate. May get to distant site but environment may not be appropriate for growth of those cells. – Incorrect receptors – Metabolic factors – Failure of angiogenesis 21  ANGIOGENESIS Once a tumour has reached 1-2mm3 it’s growth is halted due to lack of nutrients/oxygen. This alters the tumour’s microenvironment, making it hypoxic. This causes the upregulation of pro-angiogenesis factors, e.g. angiopoietin, VEGF. This causes the growth of new, thin wall blood vessels that not only allows for the continued growth of the tumour but provides another opportunity to enter the bloodstream as well. Therapeutic target – Thalidomide in renal cancer 22  METASTASIS Primary = the site where the malignant neoplasm arises eg. breast, stomach. Secondary = metastasis eg. Breast carcinoma that has spread to another organ. 23  WHAT ARE THE ROUTES OF METASTASIS? Lymphatics Blood vessels Coelemic spaces 24  LYMPHATICS Spread to local and distant lymph nodes Frequent route of spread of carcinomas Can involve lymphatics of the lung 25 26  VASCULAR SPREAD Spread through capillaries and veins to various organs. Common sites are lung, liver, bone and brain 27  VASCULAR SPREAD To Lung Can occur with a wide range of malignant neoplasms. Sarcomas eg. Osteosarcoma Carcinomas eg. breast, stomach, large intestine Kidney (cannonball) Testis eg. malignant teratoma 28 29 30  VASCULAR SPREAD To Liver Common site for carcinomas of large intestine (portal vein). Bronchial carcinoma. Breast Carcinoma. 31 32 33  VASCULAR SPREAD To Bone Can cause destruction of bone, leading to pathological fracture Bronchial carcinoma Breast carcinoma Thyroid carcinoma Renal carcinoma Cause production of dense bone (osteosclerosis) Prostate 34 35  VASCULAR SPREAD To Brain Cause a wide range of neurological symptoms and act as a space occupying lesion (SOL) Metastasis from. Bronchial carcinoma Breast carcinoma Testicular carcinoma Malignant melanoma 36 37  WHAT EFFECTS DO TUMOURS HAVE? Depends on: site of tumour extent of local spread site of metastasis extent of metastatic spread functional effects 38  WHAT EFFECTS DO TUMOURS HAVE? In certain sites a small tumour can have devastating effects People can survive for some time with very extensive metastatic spread 39  LOCAL EFFECTS OF BENIGN NEOPLASMS Cause compression - pressure atrophy - altered function eg.pituitary In a hollow viscus cause partial or complete obstruction. Ulceration of surface mucosa, bleeding Space occupying lesion – brain. 40  Benign meningioma 41  Leiomyoma 42  LOCAL EFFECTS OF MALIGNANT NEOPLASMS Tend to destroy surrounding tissue. In a hollow viscus cause partial or complete obstruction, constriction. Ulceration. Infiltration around and into nerves, blood vessels, lymphatics. Space occupying lesion - brain 43 44  colon 45 46  SYSTEMIC EFFECTS OF NEOPLASMS Haematological: Anaemia – due to ulceration (benign and malignant ) – infiltration of bone marrow (leukaemia, metastasis) – haemolysis Low white cell and platelets – infiltration of bone marrow, treatment Thrombosis – carcinoma of pancreas 47  SYSTEMIC EFFECTS OF NEOPLASMS Endocrine: Excessive secretion of hormones - benign and malignant neoplasms of endocrine glands e.g. parathyroid hormone, corticosteroids Ectopic hormone secretion - ACTH by small cell carcinoma of bronchus PTH by small cell carcinoma of bronchus ADH by small cell carcinoma of bronchus 48  SYSTEMIC EFFECTS OF NEOPLASMS Skin Increased pigmentation , Gastric, others Herpes zoster , Lymphoma,others Pruritis (itching) – Jaundice – Hodgkin’s Dermatomyositis – bronchus 49 50  SYSTEMIC EFFECTS OF NEOPLASMS Neuromuscular Problems with balance Sensory/sensorimotor neuropathies. Myopathy and myasthenia. Progressive multifocal leucoencephalopathy. May mimic metastasis to brain 51  SYSTEMIC EFFECTS OF NEOPLASMS Mechanisms largely unknown: Cachexia – Loss of weight, muscle atrophy, loss of appetite in someone who is not actively trying to lose weight Malaise – A feeling of general discomfort or uneasiness Pyrexia - Fever 50  WHY DO NEOPLASMS KILL PEOPLE? Local effects: raised ICP, perforation, hemorrhage - Benign or malignant Replacement of essential body organs. bone marrow, lung tissue, liver parenchyma (Malignant neoplasms). 51 54