YR1 Lecture 1H - Introduction to Neoplasia - Dr Tristan Rutland 2022 PDF

Introduction to neoplasia Dr Tristan Rutland Liverpool Hospital and Western Sydney University. 1 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 2 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 3 Adaptive growth respo...

Introduction to neoplasia Dr Tristan Rutland Liverpool Hospital and Western Sydney University. 1 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 2 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 3 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 4 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 5 Adaptive growth responses -revision Hyperplasia Hypertrophy Atrophy Autophagy Metaplasia 6 General Aspects of Tumour Pathology 7 1.05 Cancer is Darwinism (evolution) on an extremely shortened timescale. 8 Learning objectives Definitions & classification Biological features Cancer development Carcinogenesis Neoplastic growth and spread Grading and staging 9 Definitions Neoplasm New growth of cells Tumour Neoplasia presenting as a mass/lesion (technically a mass, but now commonly associated with neoplasms) 10 Classification & Nomenclature: Histogenesis - malignant Epithelial → Carcinoma Soft tissue/bone → Sarcoma Smooth muscle, fat, fibrous, skeletal muscle, synovium, cartilage, blood vessels Mixed tumour (one tissue with metaplasia) E.g. carcinosarcoma CNS Dependent of cell type E.g. glioma vs neuroepithelial vs meninges Germ cells → Blastoma (from 1 germ layer) → Teratoma (from several germ layer) Lymphoid/haemopoietic Neuroectodermal Melanoma 11 Classification & Terminology Benign Malignant - Glandular Adenoma Adenocarcinoma - Ductal Adenoma Adenocarcinoma - Squamous Papilloma Squamous cell carcinoma - Transitional Papilloma Transitional cell carcinoma Smooth muscle Leiomyoma Leiomyosarcoma Fat Lipoma Liposarcoma Fibrous Fibroma Fibrosarcoma Skeletal muscle Rhabdomyoma Rhabdomyosarcoma Cartilage Chondroma Chondrosarcoma Vascular Haemangioma Angiosarcoma Bone Osteoma + etc Osteosarcoma + etc. Epithelial 12 Classification & Terminology (Cont’d) Benign Malignant Melanocytes (Neuroectodermal) Naevus Melanoma Germ Cell Benign Teratoma Malignant Teratoma Lymphoid Lymphoid hyperplasia Lymphoma 13 Benign vs malignant (what does that mean!). In general* Malignant = bad → rapidly growing and spreading tumour Malignant = CANCER Benign = good → Slow growing, not invasive Three main features favour malignant neoplasms differentiation and anaplasia The more ugly it looks and less like original tissue Differentiation →how much do it look like the original tissue Anaplasia →how ugly does it look local invasion It is able to move through the tissue Expresses various enzymes to “dissolve” surrounding tissue Metastasis It spreads to another organ or site (not joined to original tumour). *there are always exceptions 14 Example: Differentiation Well Differentiated (looks similar) Tumour Original 15 Poor differentiation Tumour Original 16 Anaplasia Anaplastic tumour cell Normal cell (lymphocyte) 17 Invasion Malignant Benign 18 Invasion Malignant Benign 19 Metastasis (example colorectal carcinoma) Primary tumour Metastasis 20 Metastasis to a benign tumour! (lung cancer to a meningioma) 21 HOWEVER Sometimes a benign tumour can kill a patient if it is in the wrong place. Some “benign tumours” can invade. Some malignant tumours will not metastasize. NOTHING IS 100% in medicine “Never say never and Never say always” 22 Biological characteristics of tumours 23 1.10 Principles Cancer is a genetic disorder caused by DNA mutations, etc Genetic alterations in cancer cells are heritable (passed on) This is were Darwinism kicks in! The best suited clone survives Mutations and epigenetic change the cell Gives it a set of properties that are referred to collectively as cancer hallmarks. Phenotype of cancer Allows for targeted treatments in some cases. 24 Most cancers develop in a stepwise fashion Hyperplasia/Metaplasia No mutations Low grade dysplasia Some mutations, confined to BM High grade dysplasia More mutations, confined to BM Malignant tumour Mutations allowing invasion 25 Mitosis is risky business Numerous checks and balances to minimize errors being passed on. We don’t want damaged cells to replicate. The process of mitosis is risky in itself, e.g. Can generate mutations by incorrect bases Body has a number of checks/double checks/repair/self destruct mechanisms to avoid this! 26 Cancer Genes Recurrently affected genes that are involved in cancer Normally work together in body to provide homeostasis When they are altered (constantly turned on or off), problems arise! Four major types: Oncogenes Tumor suppressor genes Genes involved in apoptosis Immune related genes (newest concept) Not covered in depth today 27 Oncogenes Arise from mutated proto-oncogenes: proto-oncogenes are normal genes and are usually pro-growth and enhanced survival Usually part of cell signaling pathway If these proto-oncogenes are mutated or overexpressed Constantly “switched on” Activates pathway (or increases factors) Increase growth and survival of cell Can ignores off signals (if mutated gene downstream from other genes) 28 Examples (clinically relevant) (don’t need to learn all, just a flavour!) RAS Signaling pathway Mutation – prognosis and treatment failure BRAF Numerous tumours (melanoma, colorectal, etc) Can be targeted in some tumours (melanoma) Prognostic markr HER2 Amplification → breast and gastric cancers MYC Amplification → certain lymphomas and neuroblastomas 29 Tumor suppressor genes Ultimate aim is prevent uncontrolled growth of altered cells. We have two copy of these genes So need both copies lost to lose effect of gene Two major roles: Governors vs guardians Governors Stops cells proliferating if too much damage Guardians Sense damage Try and repair or induce apoptosis (if unable to) 30 Examples (clinically relevant) (don’t need to learn all, just a flavour!) Retinoblastoma gene aka RB TP53 Neurofibromin-2 aka NF2 Adenomatous Polyposis Coli aka APC 31 32 Genes involved in apoptosis Two types: Protect against apoptosis vs promote/induced apoptosis Protect against apoptosis Stop cells from undergoing apoptosis i.e. enhancing cell survival Tell cells to ignore apoptotic signals Promote/induced apoptosis Usually under expressed or inactivated 33 Tumours need the following to develop and progress Mutations of certain genes* Fundamental driving force Automatous Avoid the immune system Immortalised Loss attachment to other cells *Majority of tumours (some will have silencing or translocations) Alteration (mutations) of certain genes* Mutations in certain genes Genes that repair DNA damage, stop cell cycle and/or initiate apoptosis. Activate genes that promote growth and survival Other mechanisms apart from mutations Translocations Amplification Epigenetic Silencing In general More alterations of cells DNA = more genetically unstable cell 35 Mutations lead to… Automatous →Do not respond to bodies commands (e.g. no longer rely on hormones (or lack of)) and can multiple without external signals. NB some tumours can remain sensitive to certain hormones, like oestrogen (and the risk factors for these tumours are usually abundance of these hormones!) Avoid the immune system (the body doesn’t like cancer cells!) They produce weird antigens→ attacked by immune system Immortalised (activation of telomerases). Normally only found in stem cells. Loss attachment to other cells (and basement membrane) Allows cells to move around more (like invade!) 36 Two hit hypothesis Tumour suppressor genes have two copies (basic genetics!) Both copies lost to lose effect of gene Patients with autosomal dominant (AD) cancer syndromes have a increased risk of tumours. FAP → APC gene Lynch → Mismatch repair genes 37 One Hit vs Two Hit Tumor Cell X X X X X X X X X X X X XX X X X X X X X X X X X X X X X X X X X XX X X XX X X X X X XX X X X XX X X XX X X XX X X XX X X X X X X X X X X X X X X X X X Need “Two-Hits” to develop Tumour X X XX X X X X X X X X X XX X X X XX X X X XX X X X X X X X X X X X X X X X X X X XX X X XX X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Inherit “One-Hit” therefore only need “One-Hit” in good allele to develop tumour 38 Original slide Associate Professor Joanne Lind lecture Biological characteristics Clonality – Monoclonal* I.e all the cells (initially) have the same genetic mutations….. Growth Cell cycle dependent Cells replicate during growth phase of tumour, but by the time a cancer is detected, most cells are no longer replicating Proportional to growth fraction (GF) GF affects response to chemo/radiotherapy Mitoses may not reflect growth rate Cell proliferation > Cell loss *Initially 39 Biological characteristics Cellular (tissue culture) features Loss of cell-to-cell contact, density inhibition, anchorage dependence, cohesiveness ↓ serum (growth factor) requirement Fail to mature; are immortalised and transplantable. Host factors: Hormonal influence Tumours that arise from hormonally responsive tissues can also be hormonally responsive Hormonally responsive tumours have favourable but often temporary response 40 Cancer development Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. Cancer development: 4 Phases 1. Transformation 2. Growth 3. Invasion 4. Metastasis 42 Cross, Simon S. Underw ood's Pathology : A Clinical Approach. Seventh ed. 2019. Web. Cancer development Natural history: Transformation (essential precursor change in the cell) ↓ Growth (of transformed cells) ↓ (Normal → hyperplasia/metaplasia → dysplasia → malignant neoplasia) Invasion ↓ ↓ Metastasis Associated molecular genetic changes and differential expression of proteins produced by oncogenes *can arise de-novo 43 Cancer development 1. Transformation - Predisposing factors 2. Growth - Morphological changes 44 Cancer development - Transformation: Predisposing factors Age Environmental - Physical, chemical, biological - DNA damage (e.g. radiation/inflammation) Heredity - ↑relative risk by 3x if family member has cancer - Dominant - e.g. FAP - Recessive - chromosomal instability e.g. skin cancers - Complex 45 Cancer development - Transformation : Process of carcinogenesis Multi-step progression. Initiation ↓ Carcinogens alter proto- and/or suppressor oncogenes 46 Cross, Simon S. Underw ood's Pathology : A Clinical Approach. Seventh ed. 2019. Web. Cancer development - Transformation: Normal cell → DNA Damage/ → DNA repair failure → Cell genome mutations alteration ↓ ↓ ↓ ↑growth ↓tumour promoting genes* suppressor genes ↓ ↓apoptosis genes ↓ ↓ ↑ cell growth↓ apoptosis ↓ ↓ Genomic instability → ↑ Mutations → Clonal expansion ↓ Neoplasm ↓ Malignancy *Oncogenes 47 Cancer development - Transformation: Aetiology – Specific factors Chemical carcinogenesis Radiation carcinogenesis Viral carcinogenesis Inflammation 48 Cancer development - Transformation: Chemical Carcinogenesis Mutagenic Direct action or via enzyme activation Involve oncogenes or tumour suppressor gene Mechanism Initiation Dose dependent, rapid, irreversible, has memory, permanent DNA alteration Promotion Non-mutagenic, non-oncogenic Inactive and reversible only if before initiation occurs Time dependent 49 1.25 Cancer development - Transformation: Chemical Carcinogens Complete carcinogens Causes both initiation and promotion. Initiator carcinogens: Alkylating agents, polycylic hydrocarbons, naturally occurring (nitrosamines, aflatoxin etc) Promoter carcinogens: Cyclamates, oestrogen 50 Chemical Carcinogenesis: Common tumours Leukaemias/lymphomas Alkylating drugs (cyclophoshamide, busulphan etc) Skin cancers Arsenic Bladder cancers Aromatic amines (dyes, rubber) Smoking Lung cancer Smoking, radiotherapy, asbestos, arsenic, nickel Mesothelioma Asbestos 51 Cancer development: Radiation Carcinogenesis Radiation is mutagenic Dependent on type of radiation, dose & delivery rate, ability of DNA repair Carcinogenesis occurs when DNA repair fails Common radiation induced tumours UV radiation SCC, BCC, melanoma Ionising radiation Leukaemia, thyroid cancers Breast, lung, salivary gld cancers Skin, bone and GI cancers 52 Cancer development: Viral Carcinogenesis Oncogenic DNA viruses Viral genome integrates into host genome and becomes stabilised Viral genes are interrupted during integration and replicative cycle is incomplete Viral genes can remain dormant (latent) but can later transform cells, resulting neoplasia Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 53 Cancer development: Viral Carcinogenesis Oncogenic RNA (retro) viruses Acute transforming virus Integrated with host cell DNA and transcribed to form new DNA sequences (v-onc DNA) resulting in neoplasia Eg sarcoma viruses in birds and rodents Slow transforming virus Integrated with host cell DNA and transcribed to form v-promoter DNA – expression of this promoter gene can result in neoplasia Eg mouse mammary tumour virus (MMTV), mouse leukemia virus Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 54 Cancer development: Viral Carcinogenesis DNA viruses HPV Skin cancers (HPV-5) Cervical, H+N, other gentioanal carcinomas (HPV-16 & HPV-18) EBV Burkitt’s lymphoma NPC HBV HCC Merkel cell polyomavirus Merkel cell carcinoma RNA virus HTLV-1 Lymphomas/leukaemia 55 Inflammation and neoplasia Inflammation-related cellular damage, e.g. ROS Matrix proteases Others, e.g. Bacterial (colon), dysbiotic intestinal microbiota → Can produce reactive metabolites Leads to DNA damage (mutations) Also increased cell turnover Compounds above Examples: Inflammatory bowel disease-associated carcinomas Marjolin ulcer → SCC in chronic draining sinuses Lymphomas in hashimoto's thyroiditis 56 Cancer development and carcinogenesis Example using skin cancers Most skin cancers in Australia are caused by sun exposure (i.e. radiation). These tumours are all associated with UV light (decreasing order of frequency): Basal cell carcinoma (very common) Squamous cell carcinoma Melanoma Merkel cell carcinoma UV radiation (most common in Australia) Merkel cell polyomavirus (rest of the world) 57 Cutaneous squamous cell carcinoma UV radiation the commonest cause in Australia of this tumour (in non-skin sites, HPV/smoking/alcohol commonest causes) Other causes include: Radiation Chronic inflammation Burns Sinuses tracts Viruses Topical carcinogens (chemicals) Arsenic Chronic immunosuppression* Certain genetic disorders* *Have additive effect with above58 “Normal” 59 Dysplasia (Bowens disease/Squamous cell carcinoma in situ) 60 Squamous cell carcinoma 61 70 year-old male, 10 year Hx of chronic osteomyelitis Now 3/12 growing mass at site of sinus 62 63 Colorectal carcinoma as a model for malignancy (80% of tumours) 64 “Normal” 65 Low grade dysplasia 66 High grade dysplasia 67 Invasive carcinoma 68 Thank you 69 EXTRA slides Morphological appearances of neoplasia 70 Benign neoplasm: Pathology Macroscopic appearance Organ enlargement Compression of adjacent organs Smooth border Complications: Tumour rupture, torsion, haemorrhage Eg. Leiomyoma Compression of local or vital structures Benign leiomyoma CNS tumours 71 Benign neoplasm: Pathology Microscopic features: Resemble cells of organ of origin* i.e. welldifferentiated** Circumscribed border with a layer of fibrous tissue/compressed normal tissue *Some reactive benign tumours can look “wild”! **You can have well-differentiated malignant neoplams 72 Malignant neoplasm Morphological features Growth ↑ (inverse with differentiation) – highly variable Anaplasia DNA ↑ (aneuploidy, polypoidy), N:C ratio ↑, Nucleoli ↑ Mitoses ↑ - atypical, giant cells, disorderly arrangement Functional characteristics Invasion Infiltrates and destroys surrounding tissues collagen > elastin > cartilage lymphatic > vein > artery Metastasis Pathways → Serosal, lymphatic, haematogenous 73 Malignant neoplasm: Pathology Macroscopic appearance Organ enlargement Infiltration into adjacent organs Complications: Tumour rupture, torsion, haemorrhage Fistula Disseminated disease Infiltrating breast carcinoma 74 Malignant neoplasm: Microscopic Differentiation is variable Well-differentiated Tumour cells resemble cells of organ of origin Growth pattern is similar Poorly differentiated Few cells resemble cells of organ of origin Growth pattern unrecognisable Infiltrative border → Invades through basement membrane into normal tissues 75 1.15 Malignant neoplasm: Microscopic Nuclear:Cytoplasmic (N:C) ratio is high Big nuclei in relation to cytoplasm Cellular and nuclear pleomorphism Variation in size and shape Due to changes in cell growth and cell death Necrosis Can cause haemorrhage due to vessel damage High mitotic index Tumour cells proliferating rapidly 76 Malignant neoplasm: Microscopic Tumour behaviour Lymphatic invasion E.g. Breast carcinoma Vascular invasion E.g. Hepatocellular carcinoma Neural invasion E.g. Pancreatic carcinoma 77 Malignant neoplasm: Microscopic Tumour survival Angiogenesis: Formation of new vessels to allow tumour growth Host response to tumour Desmoplastic reaction → Fibroinflammatory reaction to the tumour cells Tumour infiltrating lymphocytes and macrophages, granulomas 78 Cellular changes in cancer Chromosomal (karyotypic) changes Abnormal number of chromosomes Haploid - Normal number of chromosomes in a somatic cell Diploid - 2X no. of chromosomes in somatic cells (this is normal) Euploid - Multiples of haploid (eg triploid etc) Aneuploid - Deviation from euploid (↑ genes within chromosomes) Usually random in most tumours Specific and non random in some tumours: Balanced translocation Tumours can have bland or unusual morphologies E.g. synovial sarcoma, Mucoepidermoid carcinomas Gene amplification (neuroblastoma) Deletions (retinoblastoma, Wilm’s tumour, leukaemia) 79 Cancer development 1. Transformation - Predisposing factors 2. Growth - Morphological changes 80 1.30 Cancer development: Morphological changes Hyperplasia Common, non-specific and potentially reversible Increase in tissue content with proliferation of normal cells Outcome Reverses back to normal when initiating factor is removed Can progress to metaplasia, atypical hyperplasia or dysplasia Metaplasia Common, non-specific and potentially reversible Arise from hyperplasia or denovo Alteration of normal tissues to another tissue type as a reactive phenomenon to an irritating external stimulus eg. Chronic gastritis Outcome Reverses back to normal when initiating factor is removed Can progress to dysplasia 81 Cancer development: Morphological changes Dysplasia Tissue acquires morphological features similar to neoplasia but to lesser and variable degrees In some organs, its counterpart is atypical hyperplasia Often have mutations (e.g. APC loss in tubular adenomas) Outcome Seldom reverses back to normal Progresses to insitu and invasive neoplasia 82 Example: APC 83 Cancer development: Morphological changes Dysplasia Different routes of progression: CRC: Normal ↓ Adenomas (dysplasia) ↓ Carcinoma insitu ↓ Invasive carcinoma Some inherited CRC: normal → hyperplastic polyp →serrated adenoma (dysplasia) → invasive carcinoma 84 Cancer development and progression Example Endometrial cancers Normal ↓ Hyperplasia without atypia Hyperplasia ↓ Atypical hyperplasia ↓ Invasive carcinoma (NB: no metaplasia and dysplasia) Atypical hyperplasia 85 Adenocarcinoma Cancer development: Morphological changes Intraepithelial neoplasia Neoplastic changes in a confine tissue compartment ranging from low to high grade CIN 1 ↓ CIN 2 ↓ CIN3 ↓ SCC Example Cervical neoplasia 86 Cancer development: Morphological changes Intraepithelial neoplasia Outcome Seldom reverses back to normal Remains stable Progresses to insitu and invasive neoplasia 87 Cancer development Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 88 1.35 Cancer development Natural history: Transformation (essential precursor change in the cell) ↓ Growth (of transformed cells) ↓ (Normal → hyperplasia → metaplasia → dysplasia → benign neoplasia) Invasion ↓ ↓ (malignant neoplasia) Metastasis 89 Cancer Development: Invasion and Metastasis 90 Invasion and Metastasis Microscopic foci of cancers cells are common in circulation but most do not establish metastatic foci Micrometastasis have already occurred at the time of clinical diagnosis Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 91 Tumour invasion: Mechanisms 92 Invasion Dependent on: Tumour cell motility Secretion of proteolytic enzymes Decreased cellular adhesion Tumour cells secrete matrix metalloproteinases (MMP) Eg collagenases, gelatinases, stromelysins Host counteracts MMP by producing tissue inhibitors of metalloproteinases (TIMP) 93 Invasion: 3 stages Attachment to BM & IM (extracellular matrix - ECM) Degradation of ECM Tumour cell migration through ECM Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 94 Invasion: Stage 1 Attachment to BM & IM (ECM) Cancer cells dissociate with downregulation of E-Cadherin (which keep cells adhered to one another) Cancer cells attach to laminin and fibronectin via receptors Receptor density correlates with invasion 95 1.40 Stromal matrix – tumour interactions Tumour cells produce MMP or induce stromal MMP to breach the basement membrane (BM) to invade the stroma / interstitial matrix (IM) BM components: Collagen type IV (C-IV)→ structure and scaffold Proteoglycan (heparan-sulfate) → fluid binding (shape) Laminin → binds C-IV, proteoglycan, epithelial cells 96 Invasion Tumour cell growth (clonal expansion) ↓ Adhesion and invasion of BM ↓ Invasion into extracellular matrix (ECM) 97 Invasion: Stage 2 Degradation of ECM Invading cells degrades the ECM by forming a host of matrix cleavage products Cancer cells secrete or activate proteases: MMP Type IV collagenase → high metastatic potential Plasmin → ECM lysis Type I collagenase Cathepsin D (a proteinase) → correlates with poor prognosis Matrix cleavage products are also Angiogenic, chemotactic, growth promoting 98 Invasion: Stage 3 Tumour cell migration through ECM ↓ cell cohesion Formation of invasive groups of cells ↑ cell locomotion by: Chemotactic ECM products Cytokines 99 Invasion and Metastasis Tumour cell growth (clonal expansion) ↓ Adhesion and invasion of BM ↓ Invasion into extracellular matrix (ECM) ↓ Vascular invasion (Metastastic potential) 100 Meng, F., Wu, G. The rejuvenated scenario of epithelial–mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev 31, 455–467 (2012). 101 Invasion →→ Metastasis Vascular invasion ↓ Interaction with host immunity ↓ ↓ ↓ ↓ Metastasis 102 Interaction with host lymphoid cells and Vascular dissemination NK/T cells controls circulation of cancer cells Cancer cells form platelet-adhesive clumps in the circulation to protect themselves from NK cells ↓ cell cohesion Pattern of vascular spread is related to: Anatomy (eg CRC → liver) Homing receptors Allowing some tumour spread not related to anatomy (eg prostate ca → bone) Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 103 Fares, J., Fares, M.Y., Khachfe, H.H. et al. Molecular principles of metastasis: a hallmark of cancer revisited. Sig Transduct Target Ther 5, 28 (2020). 104 Invasion →→ Metastasis Vascular invasion ↓ Interaction with host lymphoid cells ↓ Tumour cell embolus ↓ Adhesion to & invasion of distant vascular BM ↓ Extravasation and invasion into ECM ↓ Metastatic tumour deposit 105 Tumour spread and metastasis: Pathological observations 106 1.45 Tumour spread and metastasis Routes: Direct Invade into adjacent viscera Seeding through body cavities CSF, transcoelomic (pleural & peritoneal cavities), bladder, bronchial Vascular Lymphatic 107 Tumour spread and metastasis Distribution and patterns of metastasis Certain organs more frequently involved by metastasis eg. Liver, lungs, bone, adrenal glands, regional lymph nodes Despite some organs are very vascular, they are not frequently involve by metastasis eg. Kidney, heart, skeletal muscle Sites for metastasis are depended on its suitability (congeniality) for the metastatic cancer cells to survive and grow (Paget’s “Seed and soil” hypothesis in 1889) Cross, Simon S. Underwood's Pathology : A Clinical Approach. Seventh ed. 2019. Web. 108 Tumour spread and metastasis Distribution & patterns of metastasis (Cont.) Dependent on vascular drainage patterns organ-specific factors general metabolic/hormonal microenvironment specific features of cancer cell types Cancer cells may not necessarily survive and proliferate in any tissue in which they are entrapped Some tumours have unpredictable patterns of metastasis eg. melanoma. 109 Patterns of metastasis Bone mets: Lung, renal, breast, prostate, thyroid (follicular), adrenal (neuroblastoma only) cancers Usually osteolytic except prostatic ca. (osteoblastic) Skin mets: Bronchus, breast, melanoma Adrenal mets: Bronchus, breast Ovaries: Breast, gastric mucinous ca, colon Gut: Melanoma 110 Other unique tumour behaviour Latency and dormancy Latency Primary tumour lie low for long periods Dormancy Metastatic tumour lie low for long perods Spontaneous regression Neuroblastoma, melanoma, renal carcinoma 111 Tumour-Host Interactions 112 Tumour Effects on Host Site Pressure effects Obstruction Infection Haemorrhage Function Exaggeration – due to increased hormones Cachexia Paraneoplastic syndromes 113 Tumour Effects on Host Cachexia Due to TNF-α BMR normal or raised Loss of both muscle & fat High calorie loss and protein catabolism Paraneoplastic syndromes Abnormal production of hormones by tumour cells 114 1.50 Tumour Effects on Host Paraneoplastic syndromes Cortisol (Cushing’s) Small cell ca lung Thyroid medullary ca Pancreatic endocrine tumour Carcinoid ADH (Low sodium) Lung ca Hypercalcaemia Lung SCC; breast ca; renal ca Polycythaemia Renal ca; cerebellar haemangioblastoma; HCC Carcinoid syndrome Carcinoid – GI, lung, pancreas, thymus Hypoglycaemia Sarcoma; HCC 115 Tumour Effects on Host Paraneoplastic syndromes (non-hormonal) Neuromyopathic Myasthenia; encephalo-neuropathy Dermatopathic Dermatomyositis; acanthosis nigricans Bone/joint/soft tissue Hypertrophic osteoarthropathy; clubbing Blood & vascular Thrombophlebitis migrans; marantic endocarditis; anaemia; leukaemoid reaction; DIC Immune complex disease Nephrotic syndrome 116 Tumour-Host Interactions: Host defence Tc cells Sensitised cytotoxic T cell React to cancer neoantigens NK cells Nonspecific killing of tumour cells Direct or antibody-dependent cellular cytotoxicity (ADCC) Macrophages Nonspecific killing (endotoxin activated) or specific TH lymphocyte activation (γinterferon) by ADCC or cytotoxins Kumar, Vinay , Abbas, Abul K., Editor, Aster, Jon C., Editor, and Perkins, James A., Illustrator. Robbins Basic Pathology. Tenth ed. 2018. Web. 117 Tumour-Host Interactions: Host defence Significance of immunocompetence in host defence against tumours: Cancers more likely in congenitally immune-deficient hosts High cancer rates in immunosuppressed transplant recipients High cancer incidence in HIV-positive patients Malignant lymphoma (esp immunoblastic lymphoma) is the commonest form of cancer in immunocompromised. 118 Laboratory investigations Histopathology and cytology Immunohistochemistry Serology Electron microscopy Flow cytometry Molecular diagnosis DNA/RNA probes Gene rearrangement studies 119 1.55 Tumour markers Some genes and proteins can be useful diagnostic markers, prognostic and treatment indicators Examples Receptors HER-2 status Translocations EWSR1/FLI Hormones ER/PR Loss of enzymes MSI in CRC 120 Clinicopathological staging of tumours 121 Grading & Staging Grading Based on differentiation / anaplasia Staging Based on Size of primary (+/- specific local involvement) = T stage Lymph node spread (and extent) = N stage Haematogenous spread = M stage 122 Clinicopathological staging of tumours Information from pathological examination of a tumour is important for clinical staging Clinicopathological staging is important for prognostication and treatment 123 Clinicopathological staging of tumours Important pathological information: Tumour type Tumour differentiation Patterns of growth Tumour size Extent of tumour invasion into primary organ and surrounding tissues Presence of lymphatic and vascular invasion Presence of perineural invasion Presence of predisposing lesions Presence of local lymph node metastasis 124 The End 125