Tumor Metastasis Lecture Notes PDF

Neoplasia Tumour Metastasis Dr Sarojini Devi MB52 Blk1 Learning Outcomes 1. 2. 3. 4. Define metastasis (C1) Explain metastatic sequence with a suitable diagram (C4) Explain tumour invasion and pagetoid infiltration (C2) Explain various routes of metastases with clinical examples (C2) Manipal Univers...

Neoplasia Tumour Metastasis Dr Sarojini Devi MB52 Blk1 Learning Outcomes 1. 2. 3. 4. Define metastasis (C1) Explain metastatic sequence with a suitable diagram (C4) Explain tumour invasion and pagetoid infiltration (C2) Explain various routes of metastases with clinical examples (C2) Manipal University College Malaysia 2 Definition Spread of tumour from a primary site and its establishment at a distant secondary location Mortality in cancer patients may be attributed to tumour metastases Manipal University College Malaysia 3 Metastasis It can occur via blood, lymphatics or within body cavities It is a complex multistep process – only a small % of tumour cells complete all steps to successfully metastasize After 24 hr. in circulation - < 0.1% tumour cells survive; < 0.01% survive to form metastasis But it only takes ONE cell Two phases to the metastatic cascade: 1. Invasion of ECM 2. Vascular dissemination, tissue homing and colonization Manipal University College Malaysia 4 Metastasis: Multistep process 1. Detachment of tumour cells from neighbour cells 2. Invasion of surrounding connective tissue to reach blood and lymphatic vessels 3. Intravasation into lumen of vessels 4. Evasion of host defense mechanism (natural killer cells) 5. Adherence to endothelium at a remote location 6. Extravasation of tumour cells from vessel into surrounding tissue 7. Survival and growth in new environment Manipal University College Malaysia 5 Tumour Invasion Single most important criteria for malignancy Metastasis is a consequence of invasion Epithelial tumour – invasion easily recognised – basement membrane serves as clear line of demarcation Connective tissue tumours – invasion is less easily recognised – no distinction Manipal University College Malaysia 6 Tumour Invasion of ECM (extracellular matrix) Tissue compartment are separated by 2 types of ECM Basement membrane Interstitial connective tissue – combination of collagen, glycoproteins, proteoglycans Invasion of ECM – initiates metastatic cascade Manipal University College Malaysia 7 Invasion – Critical step in Metastasis Defined by 3 major steps in tumour invasion of ECM 1. Loosening of intercellular junctions Loss of E-cadherin function (cell adhesion molecule) 2. Degradation of ECM Proteolytic enzymes – matrix metalloproteases, etc. 3. Migration and invasion Multistep involving receptors and signalling pathways Manipal University College Malaysia 8 Pagetoid infiltration Invasion within epithelium – known as pagetoid infiltration Named after Paget’s disease of nipple (infiltration of the epidermis of nipple by tumour cells from ductal carcinoma of breast) Pattern seen to occur in few other epithelial malignancies ‘Pagetoid’ – term used in dermatology Refer to ‘upward spreading’ of abnormal cells in the dermis Cells display pagetoid growth when they invade the upper epidermis from below Manipal University College Malaysia 9 Pathways of tumour spread (metastasis) Dissemination of tumour cells occur through 3 pathways 1. Direct seeding of body cavities or surface (transcoelomic spread) 2. Lymphatic spread 3. Haematogenous spread Iatrogenic spread – via surgical instrument can occur – though it is RARE A reason why biopsies of testicular masses are never done Manipal University College Malaysia 10 Direct seeding & Transcoelomic spread Occur when malignant tumour penetrates a natural ‘open field’ lacking physical barriers Peritoneal, pericardial and pleural cavities Subarachnoid space Joint spaces Manipal University College Malaysia 11 Direct seeding & Transcoelomic spread (cont’d) Transcoelomic spread – spread across peritoneum Krukenberg’s tumour Characteristic carcinoma of ovary – spread to peritoneal surface – producing heavy cancerous coating Tumour cells remain confined to surface of abdominal viscera without penetrating the organ Manipal University College Malaysia 12 Direct seeding & Transcoelomic spread (cont’d) Pseudomyxoma peritonei Mucus secreting carcinomas fill peritoneal cavity with a gelatinous neoplastic mass Appendiceal carcinomas; ovarian carcinomas Gelatinous neoplastic mass Manipal University College Malaysia Ovarian carcinoma 13 Lymphatic spread Most common pathway of dissemination for carcinomas Sarcomas – rarely It follows the natural routes of lymphatic drainage Carcinoma breast Upper outer quadrant – axillary lymph nodes – to infraclavicular and supraclavicular lymph nodes Carcinoma lung Arising in major respiratory passages – perihilar, trachea-bronchial and mediastinal lymph nodes Local lymph nodes may be by-passed = ‘skip’ metastasis Manipal University College Malaysia 14 Lymphatic spread (cont’d) Sentinel lymph nodes First lymph node in a regional lymphatic to receive lymph flow from primary tumour Application: Sentinel lymph node mapping, intra-operative frozen sections and biopsies Assessment for presence /absence of metastases Manipal University College Malaysia 15 Lymphatic spread (cont’d) Tumour cells reach regional and distant lymph nodes via afferent lymphatic channels Settle and grow in the periphery of lymph node – gradually extend to replace it Metastatic lymph nodes Usually firmer and larger than normal Groups of involved nodes may be matted by both tumour tissue and connective tissue reaction May interrupt lymphatic flow – cause oedema in draining region Manipal University College Malaysia 16 Lymphatic spread: Clinical examples 1. Lymphadenopathy - commonest 2. Lymphangitis carcinomatosis (lung) Dilated, obstructed lymphatics due to tumour – seen on X-rays 3. Peau d’orange (breast) Dilated dermal lymphatics 4. Lymphoedema Distended limb due to obstructed lymphatics Manipal University College Malaysia 17 Lymphatic spread: Clinical examples (cont’d) ‘Antigens’ in draining lymph nodes may lead to enlargement (hyperplasia) of nodes Enlarged lymph nodes do not always harbour metastases Assessed on microscopic examination of involved node Manipal University College Malaysia 18 Haematogenous spread Typical of sarcomas, rarely seen in carcinomas Histologic evidence of penetration of small blood vessels at the site of primary neoplasm Usually involves veins; arteries more resistant (thicker walls) Arterial spread (may occur) - gives rise to tumour emboli Manipal University College Malaysia 19 Haematogenous spread (cont’d) Common sites include: Liver, Lung Bone, Brain Rarely metastasize to: Skeletal muscles Spleen Manipal University College Malaysia 20 Haematogenous spread (cont’d) Tumours that spread by intravenous growth: 1. Renal cell carcinoma →invades the branches of the renal vein→ grows into renal vein → grows in a snakelike fashion→ enters inferior vena cava → Rt side of the heart 2. Hepatocellular carcinomas→ penetrate portal and hepatic radicles→ grow into the main venous channels. ❖Such intravenous growth may not be accompanied by widespread metastasis. Manipal University College Malaysia 21 Manipal University College Malaysia 22 Examples: Clinical effects of metastatic malignant neoplasms 1. 2. 3. 4. 5. Lymphadenopathy Jaundice Bone pain or Fracture (pathological fracture) Cerebral stroke Cachexia, Anorexia, Lassitude Manipal University College Malaysia 23 Manipal University College Malaysia 24