Integrated Pathology (6H6Z1002) Malignant Disease Past Paper PDF 2024-25

21/10/2024 Learning outcomes Integrated Pathology (6H6Z1002): Distinguish the differences between...

21/10/2024 Learning outcomes Integrated Pathology (6H6Z1002): Distinguish the differences between benign growth disorders and malignant disease Describe the characteristics of malignant cells Malignant Disease Discuss the aetiology of malignant disease, relate specific risk factors to certain types of cancer Dr Qiuyu Wang Explain the mechanisms responsible for the disease [email protected] Understand the clinical effects of tumour Room: E248 Appraise approaches used for diagnosis and treatment of malignant disease The learning outcomes are described in each section in the MD guide. 1 2 Learning Resources Revision Reading Lakhani, S.R., Dilly, S.A., Finlayson, C.J. (2016) Basic Pathology an introduction to the mechanisms of disease. CRC Press. Chapter 16, Eukaryotic cell cycle, mitosis, and The e-book meiosis in Thrive in Cell Biology (2013). Wang Q. et al. Oxford University Press. Weinberg, R.A. (2014). The Biology of Cancer. USA: Garland Chapter 17, Cell death in Thrive in Cell Biology Science (2013). Wang Q. et al. Oxford University Press. Moodle URL link : e-book: Chapter: Cancer cell other appropriate published materials, journal articles and biolog web-sites. If these recommended resources are not available to you, you should use other resources to achieve the learning outcome! 3 4 Recap What is cancer? HeLa cells Cancer is a problem of multicellular organisms Cancer is a cellular phenomenon that occurs because cells acquire certain abnormal properties. Cancer is a collection of different diseases Cancer displays uncontrolled growth (core feature) 5 6 1  21/10/2024 Recap Terms Dysplastic nevus (atypical mole) Neoplasia: formation of an abnormal mass of proliferating cells, possessing a significant degree of autonomy. Anaplasia: lack of differentiation in neoplastic cells; seen as a mass of pleomorphic primitive cells. Hyperplasia: cell response to a specific stimulus, the proliferation of cells within an organ or tissue beyond normal; may result in the gross enlargement of an organ, the formation of a benign tumour. http://commons.wikimedia.org/wiki/File:Dysplastic_nevus_- Metaplasia: One differentiated cell type changes into another Copyright © 2007 Interactive Medical Media LLC, Precancerous Skin Lesions _add_-_high_mag.jpg mature differentiated cell type. Dysplastic nevi (DN): are atypical moles that are larger than ordinary moles Dysplasia: abnormality of development, alteration in size have irregular shape and tend to have uneven colour; usually begin as flat, but parts may raise shape and organization of adult cells. above the skin surface. show rete ridge bridging: epidermal thickenings that extend downward between dermal papillae show moderate nuclear atypia People who have DN are at increased risk of developing melanomas 7 8 Hyperplasia Hypertrophy Hypertrophy: is an increase in the size of an organ due to an increase in cell size without an increase in cell number. Physiological Pathological Physiological Pathological 9 10 Characteristics of malignant cells Learning outcomes loss of growth control (growth signal autonomy; insensitivity to inhibitory signals) resistance to apoptosis Describe the characteristics of malignant cells unlimited replicative potential (telomere, telomerase) sustained angiogenesis ability to invade the surrounding tissue ability to colonize and survive in an ectopic environment (metastasis) exhibit anchorage-independent growth and lose sensitivity of contact-inhibition Hanahan and Weinberg, Hallmarks of cancer: the next generation (2011) Hanahan, Hallmarks of cancer: new dimensions (2022) 11 12 2  21/10/2024 Growth factor signaling cascade Time-dependent change in telomere length Autocrine signalling loop Ligand-independent signalling Insensitive to growth inhibitory signals http://www.google.co.uk/imgres?imgurl=http://www.medhelp.org DKC, dyskeratosis congenita /images/articles/MSMA_Telomeres_Figure5.jpg 13 14 Telomerase activity and replicative lifespan Sustained Angiogenesis VEGF, FGF Angiogenic 1-2 mm Switch Angiostatin Endostatin thrombospondin Small tumor Larger tumor Nonvascular Vascular “Dormant” Metastatic potential Nature Reviews Cancer (2002) Griffioen and Molema. Pharmacol Rev. 2000;52:237. 15 16 Invasion and metastasis A in situ cancer B invasion of the tumour border Anchorage-independent growth in vitro Normal cells Cancer cells D intravasation of circulatory system C lymphatic spread F solitary dormant cells G progressive colonization occult micrometastases angiogenesis E extravasation Nature Reviews Cancer (2003) 3, P55-63 17 18 3  21/10/2024 Cancer cells: loss of contact inhibition Normal cells Cancer cells Hallmarks of cancer: the next generation. Cell. 2011. 144(5):646-74. Douglas Hanahan and Robert A. Weinberg. 19 20 Causes of cancer (aetiology of cancer) Learning outcomes acquisition of mutations o inborn zygotic mutations, somatic mutations environmental factors Discuss the aetiology of malignant disease, o viruses, chemicals and radiation relate specific risk factors to certain types of abnormal tissue microenvironment cancer o blood and lymphatic vasculature, fibroblasts, immune cells, extracellular matrix and signalling molecules o characterized by hypoxia others: age, lifestyle etc. 21 22 Genetic mutations and increased risk of cancers p53 and cancer Inborn zygotic mutations, somatic mutations Breast cancer and ovarian cancer: BRCA1 and BRCA2 Li-Fraumeni syndrome (LFS): p53, CHK2 Childhood cancers: Wilm’s tumour (del 11p13) Chronic myelogenous leukaemia [CML, t(9,22), Philadelphia chromosome] Retinoblastoma: RB Colorectal cancer: APC (adenomatous polyposis coli gene) https://www.nature.com/articles/s41418-018-0246-9.pdf 23 24 4  21/10/2024 BRCA1 and BRCA2 chronic myelogenous leukaemia (CML) mutations in BRCA1 and BRCA2 are associated with an increased susceptibility to breast cancer and ovarian cancer. Philadelphia (Ph) chromosome CML http://www.cancerresearchuk.org/ Genetic tests for BRCA1, BRCA2 are only available, if women have a strong family history of breast cancer. Increased growth of granulocytes (mature and precursors) BRCA1 in human breast cancer Tissue http://www.rndsystems.com/ihc_molecule_images 25 26 Rb-/- in retinoblastomas Oncogenic Viruses During the viral replication process, certain virus’s DNA or RNA affects the host cell’s genes in ways that may cause it to become cancerous. Retrovirus that uses RNA for its genetic code. During the replication process, the virus uses reverse transcriptase, which allows the virus Leucocoria retinoblastoma to change its RNA genes into DNA. o HPV (human papilloma virus): cervical cancer o Epstein-Barr virus: Burkitts lymphoma Rb-/- o Hepatitis B and C viruses: liver cancer 27 28 Human papillomavirus (HPV) and cervical cancer Epstein-Barr virus and Burkitt's lymphoma 29 30 5  21/10/2024 HBV, HCV, aflatoxin and liver cancer Polycyclic Aromatic Hydrocarbons (PAHs) liver cancer Aspergillus flavus Aflatoxin http://i1.tribune.com.pk/wp-content/uploads/2013/02/505367-fir-1360509694-473-640x480.JPG 31 32 Lung cancer Breast cancer Stomach cancer Liver cancer Oesophagus Oesophagus cancer cancer Oral cancer Oral cancer Source: SEER Cancer Statistics Review, NCI, USA Source: SEER Cancer Statistics Review, NCI, USA 33 34 Stomach cancer risk factors UV Radiation and risk of cancer Red meat contains ‘haem’ which is a pigment contained in the red blood cells. When haem is digested it forms N-nitroso compounds that have been shown to damage the cells lining the stomach. http://www.dermatology.ucsf.edu/skincancer/images/UV.gif&imgrefurl 35 36 6  21/10/2024 Nucleotide Excision Repair (NER) or “short patch” repair Xeroderma pigmentosum (XP) an autosomal recessive genetic disorder of DNA repair (NER) mutated XPA-XPG sensitive to UV-light and have a 1000-fold increased risk of developing skin cancer involves both sexes and all races, with an incidence of 1:250,000 symptoms include o irregular dark spots on the skin o development of many freckles at an early age o severe sunburn when exposed to only small amounts of sunlight o eyes that are painfully sensitive to the sun o Spidery blood vessels ‘Children of the Moon/ Children of the Night’ http://www.google.co.uk/imgres?imgurl=http://ds9.ssl.berkeley.edu/lws_gems /4/images_4/xp_lg.jpg 37 38 Bodyweight and cancer risk Cancer increases with ageing http://www.cancerresearchuk.org Source: SEER Cancer Statistics Review, NCI, USA 39 40 Top six causes of all cancers in men and women Other risk factors for specific type of cancer Cancer Research UK: from the period 1993-2007 41 42 7  21/10/2024 Multi-step cancer progression process Multistep development and progression of colorectal cancer Pharmaceutical Research: (2010) Nakayama M, Oshima M. J Mol Cell Biol. 2019 Apr 1;11(4):267-276. 43 44 Causes of cancer (aetiology of cancer) acquisition of mutations Learning outcomes o inborn zygotic mutations, somatic mutations environmental factors To describe o viruses, chemicals and radiation abnormal tissue microenvironment Histogenetic classification of tumours o blood and lymphatic vasculature, fibroblasts, The clinical effects of tumour immune cells, extracellular matrix and signalling molecules o characterized by hypoxia others: age, lifestyle etc. 45 46 Recap Classification of tumours Benign and Malignant Tumour Behavioural classification: benign or malignant Histogenetic classification: cell of origin Benign Neoplasm Malignant Neoplasm Generally Encapsulated Non-encapsulated Precise classification of individual tumours is Non-invasive Invasive important for planning effective treatment Highly Differentiated Poorly differentiatied Few Mitotic Figures Mitotic Figures Common o TNM classification Slow Growth or No Net Growth Can have rapid growth o Staging Little Anaplasia Relatively Anaplastic o Grading Non-Metastatic (by definition) Metastatic 47 48 8  21/10/2024 Recap Recap Histogenetic Classification (Classification by Cell/Tissue Type of Origin) Carcinoma Epithelial Tissue Carcinoma Connective Tissue Sarcoma Hematopoietic Tissue Leukemia & Lymphoma myeloma Nervous tissue Neuroectodermal malignancies Germinal Tissue & Mixed Teratoma Tissue Types 49 50 Sarcoma The clinical effects of tumours General effects Local effects Endocrine effects Paraneoplastic syndromes 51 52 General effects of tumours Cancer cachexia Cachexia, a multifactorial syndrome associated with numerous diseases, such as tuberculosis, AIDS, congestive heart failure and cancer. Nausea/vomiting Cancer cachexia is characterised by a progressive loss of skeletal muscle mass (sarcopenia), along with adipose tissue wasting, systemic inflammation and Poor appetite other metabolic abnormalities leading to functional impairment. Fever the presence of cancer cachexia does not depend on the tumour size. Pain cancer cachexia varies with the tumour type: in gastric or pancreatic cancer patients, the incidence is over 80%. Fatigue within a given type of cancer, the degree and extension of cachexia depends Weight loss on tumour stage. (cachexia) chemotherapy and radiotherapy may exacerbate cachexia. 53 54 9  21/10/2024 Cancer cachexia The clinical effects of tumours Tumour-induced inflammation is a major driver of cachexia, affecting the function of several tissues including skeletal muscle, fat, brain and liver. ▪ Local effects compression obstruction ulceration haemorrhage rupture perforation infarction Tsoli and Robertson, https://doi.org/10.1016/j.tem.2012.10.006 55 56 Paraneoplastic syndromes Hypercalcaemia- osteolytic bone lesions ▪ This refers to symptoms in cancer patients that are not readily explained by local or metastatic disease. hypercalcaemia endocrine effects Cushing’s syndrome clubbing of the fingers skin rashes hypertrophic osteoarthropathy peripheral neuropathy Multiple Myeloma cerebellar degeneration Bone metastasis 57 58 Mechanisms: osteolytic bone lesion in multiple myeloma Endocrine effects Osteoblast Myeloma cell Insulinoma: a tumour of the pancrea that produces RANKL: receptor activator of NF-κB excessive amounts of insulin. ligand DKK1, Dickkopf-related protein 1 DKK1 RANKL Osteoclast http://jnm.snmjournals.org/content/53/7/1091.figures-only 59 60 10  21/10/2024 Cancer Diagnosis Typical Clinical signs Learning outcome the presence of a lump in the breast or testicles, unusual bleeding, changes in a mole... Screening Pap smear test Appraise approaches used for diagnosis and Routine investigations X-rays, blood tests Imaging methods treatment of malignant disease computed tomography (CT) or conventional pluridirectional tomography; MRI (magnetic resonance imaging); PET (positron emission tomography); ultrasound Fibre Optic Scope (endoscoy) Special Investigations (tumour markers: eg. Catecholamine serum levels in neuroblastoma) Surgical biopsy (Histopathology of tissue-appearance; immunohistochemistry; histochemistry; electron microscopy) Genetic testing 61 62 Tumor Markers Malignant tumour histology ▪ Substance found in blood, urine or tissue which is associated with presence of malignancy. Loss of differentiation ▪ Possible uses: Loss of cellular cohesion Screening at-risk populations Nuclear enlargement Diagnosis of particular type of malignancy Staging extent of tumor spread Increased mitotic activity Monitoring therapy and recurrence Determining most advantageous treatment Wilms tumour Target of tumor scanning or therapy o hyperchromatic, enlarged nuclei o multipolar mitotic figures ▪ "Ideal" tumor marker test: Sensitive, specific, easily detected, marker levels correlate http://webpathology.com/image.asp with extent of disease 63 64 Tumour Markers PSA (prostate-specific antigen) Tumour marker Associated tumour types alpha fetoprotein PSA is a protein produced by the cells of the hepatocellular carcinoma, teratoma of testis (AFP) CA15-3 breast cancer prostate gland CA19-9 mainly pancreatic cancer, but also colorectal cancer and other types of gastrointestinal cancer Clinical levels correlating with stage CA-125 mainly ovarian cancer, Signals cancer recurrence after prostatectomy Calcitonin medullary thyroid carcinoma Glial fibrillary acidic Benign prostatic hyperplasia - 50-80% glioma (astrocytoma, ependymoma) protein (GFAP) Myo D1 rhabdomyosarcoma elevated prostate-specific antigen (PSA) Prostate < 4.0ng/ml is considered as normal Synaptophysin neuroendocrine tumour 65 66 11  21/10/2024 ISH Genetic Test and Personalised Medicine HER2 testing algorithm a Tumour Sample HER2 IHC b IHC 0 IHC 1+ IHC 2+ IHC 3+ HER2 ISH c ISH -ve ISH +ve Report as HER2 positive to physician for Herceptin treatment (a) CISH Immunohistochemistry (IHC) In situ hybridization (ISH) (b) SISH (c) DDISH 67 68 Liquid biopsy: circulating tumour cells (CTCs)and circulating tumour DNA (ctDNA) Management of cancers is determined by how aggressive the tumour is; predictability of its spread mortality/morbidity of patients from treatment procedure cure rate of treatment procedure Survival is usually measured as 5 year survival with no recurrence. ctDNA: detected in 82% of patients with metastatic and in 55% of patients with localized cancer of all types (Sci Transl Med. 2014 Feb 19; 6(224): 224ra24). Treatment Surgery Chemotherapy Immuno therapy Hormone therapy Radiotherapy Bone marrow transplants Gene therapy Targeted cancer therapy Proton beam therapy 69 70 Chemotherapeutic agent Chemotherapy: from world war to the war on cancer Mustard gas cisplatin Cyclophosphamide From: Naomi Elster. theguardian.com 5FU (fluorouracil) etoposide 71 72 12  21/10/2024 The inhibitory effect of cell cycle by paclitaxel What are common side effects of chemotherapy? Complex of α, β tubulin subunits and paclitaxel. J Am Coll Cardiol. 2006;47(4):708-714 73 74 Common side effects of chemotherapy Targeted cancer therapy Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with Frequent infections specific molecules involved in tumour growth and progression. Diarrhoea Also called “molecularly targeted drugs” “molecularly targeted Nausea and loss of appetite therapies”. Hair loss Targeted cancer therapies that have been approved for use in anaemia specific cancers include drugs that interfere with cell growth signalling or tumour blood vessel development, promote the specific death of cancer cells etc. Treatments based on the unique set of molecular targets produced by the patient’s tumour. 75 76 Proton therapy Human papilloma virus (HPV) vaccine Date of Country Gender(s) Target age group introduction Austria 2006 M/F 9-15 Belgium 2007 10-13 Canada 2007 M/F 9-26 (M)/9-45 (F) Denmark 2009 F 12 http://www.theguardian.com/uk-news/2015/mar/23 Proton therapy (proton beam therapy), is a France 2007 F 14-23 type of radiation treatment that uses Greece 2007 F 12-26 protons rather than x-rays to treat cancer. A proton is a positively charged particle. Italy 2007 F 12 Macedonia 2009 F 12 Doctors may use proton therapy alone, or Norway 2009 F 12-13 they may combine it with standard radiation http://www.theprovince.com/cms/binary/8880234.jpg South Korea 2007 M/F 9-15 (M)/2-26 (F) therapy, surgery, chemotherapy, and/or Sweden 2010 F 10-12 immunotherapy. UK 2008 M/F M:9-15; F:9-26 Proton therapy equipment http://upload.wikimedia.org/wikipedia/commons/7/79/Cases_of_HPV_cancers 77 78 13