Cancer Pathology (1-2567) PDF

MTH64-203E Pathology (1-2567) Neoplasia Cancer Pathology Asst. Prof. Dr. Aman Tedasen School of Allied Health Sciences, Walailak University Contact information: Academic Building 7, Room 128. Email: [email protected]...

MTH64-203E Pathology (1-2567) Neoplasia Cancer Pathology Asst. Prof. Dr. Aman Tedasen School of Allied Health Sciences, Walailak University Contact information: Academic Building 7, Room 128. Email: [email protected] Learning objectives By the end of this class, the student will be able to: Explain the epidemiology of cancer Explain the characteristics of Benign and Malignant neoplasms Explain risk factors and etiology of cancer Explain the carcinogenesis, tumor grading and staging, tumor marker cancer diagnostic and treatment of cancer 1. Breast cancer 2. Lung cancer 3. Liver cancer 4. Colon cancer 5. Cervical cancer 1  Cancer Cancer: An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) Pérez-Carreón, Julio & Meléndez-Zajgla, Jorge. (2012). In vitro and in vivo models for cancer research. Molecular Oncology Principles and Recent Advances. 148-162. 10.2174/978160805016111201010148. 2  Neoplasia and Cancer Neo = New Plasia = growth, cellular multiplication Neoplasia refers to a type of tissue growth that continues despite the absence of stimulus Tumor: “swelling” – refers to any tissue mass, solid- or liquid-filled, benign or malignant Cancer: refers to malignant tumors, which have the potential to metastasize 1. Cancer Epidemiology of New Cancer Cases and Deaths Worldwide: Cancer type and mortality rate 1 1 2 2 3 3 Sung, et al., (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 71(3), 209–249. 3 1. Cancer Epidemiology of New Cancer Cases and Deaths Worldwide: Cancer type and mortality rate 1 1 1 1 2 2 2 2 3 3 3 3 Sung, et al., (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 71(3), 209–249. 4 1. Cancer Epidemiology of New Cancer Cases and Deaths Most common cancer in Thailand Male Female 1 1 2 2 3 3 National Cancer Institute, Thailand, 2019 5  2. Characteristics of Benign and Malignant Neoplasms Tumors – abnormal growth of tissues 1. Benign tumors ◼ are slow growing and enclosed in a fibrous capsule ◼ are not malignant ◼ are given names "oma" (although a melanoma is a malignant skin cancer) 2. Malignant tumors ◼ proliferate rapidly, invading neighbouring tissues ◼ can metastasise, or spread, to other sites of the body ◼ are named using the conventions of tissue, cell type, and origin e.g. A tumour of the bone is an osteoma if benign and an osteosarcoma if malignant https://www.vectorstock.com/royalty-free-vector/malignant-and-benign-tumor-vector-26703501  2. Characteristics of Benign and Malignant Neoplasms Benign Malignant Ends in “-carcinoma” (cancer in cells of endodermal or ectodermal origin) Nomenclature Ends in “-oma” or “-sarcoma” (cancer in cells of mesenchymal origin) Growth rate Slow Fast Local No, grows as a cohesive mass encapsulated by Yes, destroys surrounding tissue and lacks a well- invasiveness dense connective tissue defined capsule Yes, except for CNS and cutaneous basal cell Metastasis* No carcinomas Differentiation Well differentiated Poorly differentiated: anaplasia Adenoma Adenocarcinoma: glandular epithelial cancer Osteoma Osteosarcoma: bone cancer Examples Squamous cell papilloma: benign skin Squamous cell carcinoma: skin cancer epithelial tumor Nomenclature  2. Characteristics of Benign and Malignant Neoplasms Definition Differentiation: refers to the morphology of cells compared to normal cells of the same tissue Well differentiated tumor cells look and function like normal cells of the tissue lymphoblast lymphocyte Poorly differentiation Poorly differentiated tumor cells (anaplastic cells) do not function like the normal tissue and appear abnormal on microscopy  2. Characteristics of Benign and Malignant Neoplasms Definition Pleomorphic Hyperchromatic Cell polarity normal cancer Anaplastic cells have the following features: Pleomorphic: continual variation in size and shape Hyperchromatic: cells are dark-staining with large nuclei Loss of polarity: normal cells are anchored and oriented to the basement membrane; anaplastic cells lose this uniform orientation and the tumor cells grow in a disorganized way Mitoses: increased proliferation results in abnormally large number of cells undergoing mitosis  2. Characteristics of Benign and Malignant Neoplasms Grading: reflects the degree of differentiation in the tumor cells High-grade tumor : poorly differentiated more aggressive Low-grade tumor Staging: reflects the size of the primary tumor and the extent of local and distant spread Early state of Cancer metastasis prostate cancer Grading and staging are used to describe the characteristics of the cancer and to determine prognosis  3. Risk factors and etiology of cancer Development of cancer Cancer : Accumulation of mutations of many genes and it takes many years to develop cancer : Multistep process - Genetic factors (5-10%) - Environmental factors (90%)  3. Risk factors and etiology of cancer Multistep chemical carcinogenesis can be conceptually divided into four stages: 1. Tumor initiation 2. Tumor promotion 3. Malignant conversion 4. Tumor progression The activation of proto-oncogenes and the inactivation of tumor suppressor genes are mutational events that result 1 2 3 4 from covalent damage to DNA caused by chemical exposures The accumulation of mutations, and not necessarily the order in which they occur, constitutes multistage carcinogenesis During these stages, progressive epigenetic changes are also occurring due to chemical exposure https://oncohemakey.com/chemical-carcinogenesis-2/  3. Risk factors and etiology of cancer What causes cancer? 3 categories of external agents, including: 1. Physical carcinogens: ultraviolet and ionizing radiation 2. Chemical carcinogens: asbestos, components of tobacco smoke, aflatoxin (a food contaminant), and arsenic (a drinking water contaminant) 3. Biological carcinogens: infections from certain viruses, bacteria, or parasites Ageing is another fundamental factor for the development of cancer, cellular repair mechanisms to be less effective as a person grows older 3. Risk factors and etiology of cancer 1. Mutations come from environmental factors Chemical carcinogens e.g., benzo(a)pyrene Radiation e.g., solar ultraviolet radiation Viruses e.g., Human papillomavirus Toxin e.g., alphatoxin 2. Mutations from genetic factors e.g., mutation of tumor suppressor gene and oncogene 3. Risk factors and etiology of cancer  Risk factor : Smoking Prevalence (%) of daily smoking for men and women https://canceratlas.cancer.org/risk-factors/ Cigarette smoke PAH, Risk factor : Smoking nitrosamine etc Cellular enzyme PAH (polycyclic aromatic hydrocarbon) - is a lipophilic molecule PAH - easily pass-through cell membrane through Induce diffusion DNA adduct - is metabolized by intracellular enzyme to become Replication carcinogen - induced DNA adduct - DNA mismatch during replication DNA repair Normal Mismatch Mismatch occurs at - Tumor suppressor gene - Oncogene - DNA repair gene Cancer development Moorthy B., et al, Toxicol Sci., 2015, Johnson D.E., et al, Nat. Rev. Dis., 2020  Risk factor: Infection INFECTIOUS AGENT CANCER TYPE Hepatitis B virus (HBV) Hepatocellular carcinoma (liver) Hepatitis C virus (HCV) Hepatocellular carcinoma (liver), non-Hodgkin lymphoma Epstein–Barr virus (EBV) Nasopharynx, some types of lymphoma Human papillomavirus (HPV) Genital organs (cervix, vulva, vagina, penis), anus, oral cavity, oropharynx, tonsil Helicobacter pylori Stomach Kaposi sarcoma herpes virus (KSHV) Kaposi sarcoma, primary effusion lymphoma Human T-cell lymphotropic virus, type 1 Adult T-cell leukemia (blood) and lymphoma Schistosoma haematobium Urinary bladder Clonorchis sinensis, Opisthorchis viverrine Cholangiocarcinoma (bile ducts) Human immunodeficiency virus (HIV)* Kaposi sarcoma, lymphoma, cervix, anus, and conjunctiva of the eye https://canceratlas.cancer.org/risk-factors/  Risk factors: body weight, alcohol consumption, diet, physical activity Alcohol consumption Unhealthy diet e.g., high amounts of sugar-sweetened beverages Physical inactivity Sedentary behaviors, including screen-time, increase risk of excess body weight, whereas aerobic physical activity, including walking, reduces risk Excess body weight increases risk of 13 types of cancer, 3.6% of all new cancer cases among adults worldwide in 2012 in 2016 an estimated 39% of men and 40% of women aged 18 years and older https://canceratlas.cancer.org/risk-factors/ Risk factor: Reproductive and reproductive hormones Sexual maturation and reproductive patterns alteration have led to increased lifetime number of monthly menstrual cycles, which is associated with higher risk of breast, endometrial and ovarian cancers Although not fully understood, one mechanism that could underlie these relationships is increased exposure to endogenous estrogen and progesterone levels Longer-term breastfeeding lowers risk of most types of breast cancer  Risk factor: Ultraviolet radiation Ultraviolet (UV) radiation is a major cause of skin cancers Keratinocyte skin cancers 13 million cases estimated each year worldwide. In rare case of fetal, keratinocyte cancers cause substantial burdens of morbidity and cosmetic concern (most occur on the face) Melanoma is a more fatal form of skin cancer with about 69,000 deaths and 350,000 cases annually worldwide Skin cancer is rare in people with innately dark skin Risk factor: Environmental and occupation exposure Asbestos is an important cause of occupational lung cancer and the unique cause of malignant mesothelioma Environmental pollution Outdoor air pollution 6-8 million deaths from lung cancer and other diseases each year. Its levels are particularly high in rapidly-growing cities in low-/middle- income countries. For example, diesel exhaust, PM2.5 Indoor air pollution Cause ~3.8 million deaths, including ~285,000 lung cancer deaths, each year in low-/middle-income countries. For example, solid fuel (e.g. wood, other biomass, and coal)  Risk factor: Carcinogen The International Agency for Research on Cancer (IARC) Monographs (www.monographs.iarc.fr) identify environmental and occupational causes of human cancer into 4 types; Group 1 : carcinogenic to humans Group 2A : probably carcinogenic to humans Group 2B : possibly carcinogenic to humans Group 3 : not classifiable as to their carcinogenicity to humans Group 4 : probably not carcinogenic to humans Genetic mutation in cancer Types of genes linked to cancer Tumor suppressor genes are genes that normally prevent uncontrolled growth and, when mutated or lost from a cell, allow the transformed phenotype to develop Often both normal alleles of tumor suppressor genes must be damaged for transformation to occur Tumor suppressor genes can be placed into two general groups; “governors” act as important brakes on cellular proliferation “guardians” are responsible for sensing genomic damage Oncogenes are genes that induce a transformed phenotype when expressed in cells by promoting increased cell growth oncogenes are mutated or overexpressed versions of normal cellular genes, which are called proto-oncogenes Most oncogenes encode transcription factors, factors that participate in pro- growth signaling pathways, or factors that enhance cell survival They are considered dominant genes because a mutation involving a single allele is sufficient to produce a pro-oncogenic effect DNA repair genes DNA damage has been long recognized as causal factor for cancer development DNA repair leads to mutations or chromosomal aberrations affecting oncogenes and tumor suppressor genes, cells undergo malignant transformation resulting in cancerous growth Genetic defects can predispose to cancer: mutations in distinct DNA repair systems elevate the susceptibility to various cancer types  3. Risk factors and etiology of cancer Genes linked to cancer: Tumor suppressor genes Are protective genes Normally, they limit cell growth by: monitoring how quickly cells divide into new cells controlling when a cell dies repairing mismatched DNA Cells growth uncontrol BRCA1, BRCA2, and p53 or TP53 modified from Christensen S.R., F1000 Faculty Rev, 2019  3. Risk factors and etiology of cancer Genes linked to cancer: Oncogenes Proto-oncogene control cell division and cell death mutation Oncogene is a mutated gene that contributes to the development of a cancer turn a healthy cell into a cancerous cell Cells growth uncontrol HER2, RAS https://www.genome.gov/genetics-glossary/Oncogene  3. Risk factors and etiology of cancer Genes linked to cancer: DNA repair genes A T G C T G C A A A G C G C G G Replication A T G C T G C A A A G C G C G G TACGACGTTT CGCGCC TACGACTTTT CGCGCC Repair DNA repair genes ATGCTGCAAAGCGCGG such as BRCA1, BRCA2, and p53 TACGACGTTT CGCGCC Morrogh L.M. and Martin P., Science signaling, 2020, Turgeon M.O., et al, Front onco, 2018, http://gcmaf.timsmithmd.com/book/chapter/60/  3. Risk factors and etiology of cancer Genes linked to cancer: DNA repair genes Normal Mutation ATGCTGCAAAGCGCGG ATGCTGCAAAGCGCGG TACGACGTTT CGCGCC TACGACTTTT CGCGCC Tyr Asp Val Ser Arg Tyr Asp Phe Ser Arg Function normally ? Tumor suppressor gene Improper function Proto-oncogene Morrogh L.M. and Martin P., Science signaling, 2020, Turgeon M.O., et al, Front onco, 2018, http://gcmaf.timsmithmd.com/book/chapter/60/  The Hallmarks of Cancer Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059.  The stage of cancer Inform cancer progression, separate into 4 stages; Stage 0: there's no cancer, only abnormal cells with the potential to become cancer Stage I: the cancer is small and only in one area (early- stage cancer) Stage II and III: the cancer is larger and has grown into nearby tissues or lymph nodes Stage IV: the cancer has spread to other parts of your body. It's also called advanced or metastatic cancer https://genesismagz.com/health-9-cancer-symptoms-to-keep-an-eye-on/ Modified from Anttila JV, et al, PLOS Computational Biology, 2019  How to diagnose cancer? 1. Tissue biopsy (Gold standard) 2. Tumor markers AFP Bence-Jones Proteins CA15-3 Calcitonin CA19-9 CA125 CEA PAP HCG NSE PSA ALP 3. Imaging test 4. Molecular techniques  Type of tumor marker Carbohydrate markers CA15-3 CA19-9 CA125 Hormones Immunoglobulin Calcitonin Bence-Jones HCG protein Type of tumor marker Oncofetal antigens AFP Enzymes CEA ALP PAP PSA NSE  Other tool to diagnose cancer Imaging test X-rays CT: Uses x-rays to produce a series of image of the body used to see if there are fractures or other types of damage to the bones. MRI: Use magnetic field and radio waves to produce a detailed picture of a patient’s soft tissue Paddock C., MedicalNewToday, 2016, https://caraccidentsinorlando.com/mri-and-ct-scan-comparison/, https://www.omegapds.com/difference-between-an-mri-ct-and-x-ray-scan/ Molecular Diagnosis Purpose: Therapeutic decision-making Melanomas with the V600E BRAF mutation respond well to BRAF inhibitors, whereas melanomas without this mutation show no response. V600E mutation is also present in carcinomas of the colon and thyroid gland, hairy cell leukemias, and Langerhans cell histiocytosis. 38 https://ccr.cancer.gov/news/article/clinical-trial-studies-therapy-for-adults-with-braf-mutant-hairy-cell-leukemia  Molecular Profiling of Tumors Molecular profiling of tumors is the future of diagnostics and therapy of cancer The technique uses DNA arrays to identify changes in DNA copy number KIT HER2 EGFR BRAF PI3K  Cancer treatment Stem cell transplantat ion eg. CAR-T cell, CRISPR *Precision medicine https://positivebioscience.com/types-of-cancer-treatment/  Cancer treatment: Surgery Surgery Remove the entire tumor removes cancer that is contained in one area Debulk a tumor removes some, but not all, of a cancer tumor Non-removing part e.g., non-visible cancer (smaller than 1 cm) Removing part of a tumor can help other treatments work better Ease cancer symptoms Surgery is used to remove tumors that are causing pain or pressure National Cancer Institute, American cancer society  Cancer treatment: Radiation therapy High doses radiation kills cancer cells or slows their growth by DNA damage Severe DNA damage over reparation stop cell dividing or die Then, cancer cells keep dying for weeks/months after radiation therapy ends External radiation Internal radiation Radioactive External radiation beam therapy injected, infused, inhaled, or ingested, and then source make their way into the bloodstream. Treatment local treatment, which means it treats a Systemic radiation target size specific part of your body Cancer skin cancer, brain tumour, prostate - Thyroid cancer: radioactive iodine - Bone metastasis from prostate cancer: radium 223 dichloride (Xofigo) Excretion No need Urine, sweat Side effect Organ collapse because radiation also hit the normal cell. Side effect depends on cancer localization e.g., taste lose, hair loss, diarrhea, and sexual problems  Cancer treatment: chemotherapy Principle: chemotherapeutic drug target rapidly dividing cell by Interfere with cell proliferation e.g., doxorubicin (DOX) inhibit cancer cell division by binding to DNA Interfere with oncogenic signal transduction and etc. Use alone or in combination with other treatment: Make a tumor smaller before surgery or radiation therapy Destroy cancer cells that may remain after treatment with surgery or radiation therapy Help other treatments work better Kill cancer cells that have returned or spread to other parts of your body Side effect: off-target e.g., hair, bone marrow and mucous membranes Sam H. Au, Sci Transl Med, 2018, National Cancer Institute  Cancer treatment: Immunotherapy Principle: helps your immune system fight cancer Why? Cancer Change protein expression specific Cannot recognize protein by immune cells Immune Cancer survive cancer CD8 T cell evasion Stop signal Apoptosis PDL-1 PD-1 Stop immune cells function Abbas A.K., et al, Cell and molecular immunology, 7th , 2012 Cancer treatment: Immunotherapy Cancer apoptosis Cancer survive Cancer apoptosis 1. Immune checkpoint inhibitors a) PDL-1 blocker 2. T-cell transfer therapy a) Find new T cell in patient blood which can recognize alter cancer  Cancer treatment: Target therapy Principle: Drug directly effect to a target Prior knowledge: What is specifically found or induced tumor in that tumor ER/PR Estrogen/ Progesterone Breast cancer Cell proliferation ER/PR ER/PR inhibitor  Cancer treatment: Stem cell transplantation Commonly use in leukemia, neuroblastoma and multiple myeloma  Cancer treatment: Precision medicine BRCA is most mutated gene that cause breast cancer (45-65%) Is also called personalized medicine Is a form of medicine that uses information about a person’s own genes or proteins to prevent, diagnose, or treat disease Confirm gene mutation at BRCA In cancer, personalized medicine uses specific information about a person’s tumor to help make a diagnosis, plan treatment, find out how well treatment is working, or make a prognosis Successful treatment Fail More than BRCA mutation cause cancer Sam H. Au, Sci Transl Med, 2018, National Cancer Institute Breast cancer  Breast cancer Pathophysiology Breast cancer develops due to DNA damage and genetic mutations that can be influenced by exposure to estrogen Sometimes there will be an inheritance of DNA defects or pro-cancerous genes like BRCA1 and BRCA2. Thus the family history of ovarian or breast cancer increases the risk for breast cancer development. In a normal individual, the immune system attacks cells with abnormal DNA or abnormal growth. This fails in those with breast cancer disease leading to tumor growth and spread. https://calgaryguide.ucalgary.ca/breast-cancer-risk-factors-causes-and-types/  Breast cancer Breast cancer can be invasive or non-invasive according to its relation to the basement membrane. Noninvasive neoplasms of the breast are broadly divided into two major types, o Lobular carcinoma in situ (LCIS) o Ductal carcinoma in situ (DCIS) https://www.saintjohnscancer.org/breast/breast-cancer/types-of-breast-cancer/  Breast cancer Sarvari, P.; Sarvari, P.; Ramírez-Díaz, I.; Mahjoubi, F.; Rubio, K. Advances of Epigenetic Biomarkers and Epigenome Editing for Early Diagnosis in Breast Cancer. Int. J. Mol. Sci. 2022, 23, 9521.  Breast cancer Witt, B.L.; Tollefsbol, T.O. Molecular, Cellular, and Technical Aspects of Breast Cancer Cell Lines as a Foundational Tool in Cancer Research. Life 2023, 13, 2311. h  Breast cancer Staging Breast cancer staging is determined clinically by physical examination and imaging studies before treatment Staging is performed to group patients into risk categories that define prognosis and guide treatment recommendations for patients with a similar prognosis Breast cancer is classified with the TNM classification system, which groups patients into 4 stage groupings based on the primary tumor size (T), the regional lymph nodes status (N), and if there is any distant metastasis (M). Hammer C, Fanning A, Crowe J. Overview of breast cancer staging and surgical treatment options. Cleve Clin J Med. 2008 Mar;75 Suppl 1:S10-6.  Breast cancer Evaluation of Patients with breast cancer needs a triple assessment using clinical evaluation, imaging, and tissue biopsy Mammography is the most commonly used modality for the diagnosis of breast cancer Most of the asymptomatic cases are diagnosed during screening mammography. Breast cancer always presents as calcifications, dense lump, with or without architecture distortion Ultrasonography is useful in assessing the consistency and size of breast lumps It has a great role in guided needle biopsy Magnetic resonance imaging has good sensitivity for describing abnormalities in soft tissues, including the breast. ▪ It is indicated if there are occult lesions, or suspicion of multifocal or bilateral malignancy, especially ILC, and in the assessment of response to neoadjuvant chemotherapy, or when planning for breast conservation surgery and screening in the high-risk patient Tissue biopsy is an important step in the evaluation of a breast cancer patient. There are different ways to take a tissue specimen, and these include fine-needle aspiration cytology, core biopsy (Trucut), and incisional or excisional biopsy  Breast cancer Cancer Antigen 15-3 or Carbohydrate Antigen 15-3 (CA 15-3) Elevated Results found in Cancer Breast** (often not elevated in early stages of breast cancer) Lung, ovarian, endometrial, bladder, gastrointestinal Non-Cancerous Reasons Liver disease (cirrhosis, hepatitis), lupus, sarcoid, tuberculosis, non-cancerous breast lesions Normal range result Normal < 31 U/ml 30% of patients have an elevated CA 15-3 for 30-90 days after treatment, so wait 2-3 months after starting new treatment to check  Breast cancer Treatment / Management The 2 basic principles of treatment are to reduce the chance of local recurrence and the risk of metastatic spread Surgery with or without radiotherapy achieves local control of cancer When there is a risk for metastatic relapse, systemic therapy is indicated in the form of hormonal therapy, chemotherapy, targeted therapy, or any combination of these Removal of axillary lymph nodes for preventing metastatic In locally advanced disease, systemic therapy is recurrence used as a palliative therapy with a small or no role for surgery  Breast cancer Hormone therapy (also called hormonal therapy, hormone treatment, or endocrine therapy) slows or stops the growth of hormone- sensitive tumors by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells Tamoxifen: Hormone receptor positive (HR+) and ERBB2 Tamoxifen (Brand Names: Nolvadex, Soltamox) Most-prescribed selective estrogen receptor modulator (SERM) An essential treatment for preventing recurrence in many patients with stage I- III breast cancer Schuurman, T. et al., (2019). Tamoxifen and pregnancy: an absolute contraindication?. Breast Cancer Research and Treatment. 175. 10.1007/s10549-019-05154-7.  Breast cancer Systemic therapy ERBB2-positive tumors receive ERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy Triple-negative tumors receive chemotherapy alone Vega Cano KS, et al., Systemic Therapy for HER2-Positive Metastatic Breast Cancer: Current and Future Trends. Cancers (Basel). 2022 Dec 22;15(1):51. Lung cancer  Lung cancer Lung cancer or bronchogenic carcinoma refers to tumors originating in the lung parenchyma or within the bronchi one of the leading causes of cancer-related deaths Smoking is the most common cause of lung cancer. It is estimated that 90% of lung cancer cases are attributable to smoking NSCLC are relatively insensitive to chemotherapy, compared to small-cell carcinoma Signs of lung cancer Chest discomfort or pain, A cough, Trouble breathing, Wheezing, Blood in sputum (mucus coughed up from the lungs), Hoarseness, Loss of appetite, Weight loss for no known reason, Feeling very tired, Trouble swallowing, Swelling in the face and/or veins in the neck Gridelli, C., Rossi, A., Carbone, D. et al. Non-small-cell lung cancer. Nat Rev Dis Primers 1, 15009 (2015). https://doi.org/10.1038/nrdp.2015.9  Lung cancer Pathophysiology hypothesized that repeated exposure to carcinogens, such as cigarette smoke leads to dysplasia of lung epithelium If the exposure continues, it leads to genetic mutations and affects protein synthesis disrupts the cell cycle and promotes carcinogenesis The most common genetic mutations responsible for lung cancer development are MYC, BCL2, and p53 for small cell lung cancer (SCLC) and EGFR, KRAS, and p16 for non-small cell lung cancer (NSCLC) https://pathologia.ed.ac.uk/topic/lung-cancer-1-pathology/  Lung cancer Staging of lung cancer Wynants, J., Stroobants, S., Dooms, C., & Vansteenkiste, J.F. (2007). Staging of lung cancer. Radiologic clinics of North America, 45 4, 609-25.  Lung cancer Lung cancer evaluation can be divided as: Radiological staging Invasive staging Imaging with PET or PET-CT directed at sites of potential metastasis when symptoms or focal findings are present or when chest CT shows evidence of advanced disease. CT Scan The significant advantage of CT is that it provides an accurate anatomic definition of the tumor within the thorax, which helps clinicians decide the optimal biopsy site Invasive Staging After CT and PET scans, the next step is to obtain tissue or pathologic confirmation of malignancy (Lung biopsy), confirm the staging and histological differentiation of cancer. One of the following procedures achieves thi Bronchoscopic endobronchial ultrasound-transbronchial needle aspiration (TBNA) Endoscopic-TBNA Mediastinoscopy Thoracoscopy or video-assisted thoracoscopy(VATS)  Lung cancer Biomarker tests available to lung cancer In small cell lung cancer, NSE and proGRP are effective markers In non-small cell lung cancer (NSCLC), CEA, SCC, CYFRA21-1, SLX and CA19-9 are commonly used for screening at least one marker among CEA, SCC or CYFRA21-1 is positive in 77% of patients with NSCLC https://www.lungevity.org/for-patients-caregivers/navigating-your-diagnosis/biomarker-testing  Lung cancer Treatment of Non-Small Cell Lung Cancer (NSCLC) The following types of treatment are used: Surgery Wedge resection: Surgery to remove a tumor and some of the normal tissue around it Lobectomy: Surgery to remove a whole lobe (section) of the lung Pneumonectomy: Surgery to remove one whole lung Radiation therapy External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq  Lung cancer Treatment of Non-Small Cell Lung Cancer (NSCLC) The following types of treatment are used: Chemotherapy uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing Targeted therapy uses drugs or other substances to identify and attack specific cancer cells Monoclonal antibodies, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and KRAS G12C inhibitors are four types of targeted therapy being used to treat advanced, metastatic, or recurrent non-small cell lung cancer EGFR (epidermal growth factor receptor) is a mutation inhibited by tyrosine kinase inhibitors erlotinib, gefitinib, and afatinib ALK (Anaplastic lymphoma kinase) includes the specific inhibitors crizotinib, ceritinib, and alectinib. A structurally similar mutation is ROS-1. The FDA recently approved crizotinib for treating cancers expressing ROS-1 mutation Immunotherapy Immunotherapy boosts the immune system and helps it recognize cancer cells as foreign, and increases their responsiveness https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq Liver cancer  Liver cancer Hepatocellular carcinoma develops from chronic liver disease caused by multiple risk factors has a strong association with chronic hepatitis B and C virus (HBV and HCV) infections Chronic hepatitis infections with other associated risk factors, including coinfection hepatitis D (HDV), alcohol consumption, cigarette smoking, may have a higher liver cancer risk Environmental exposure to aflatoxin, contaminated water with blue-green algal toxin and betel nut contribute to hepatocellular carcinoma Ethanol abuse and metabolic syndrome have been linked to liver cancer with persistent liver damage leading to steatosis, steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma Farazi, P., DePinho, R. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6, 674–687 (2006). https://doi.org/10.1038/nrc1934  Liver cancer Dhanasekaran, Renumathy & Bandoh, Salome & Roberts, Lewis. (2016). Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Research. 5. 879. 10.12688/f1000research.6946.1.  Liver cancer https://www.biorender.com/template/barcelona-clinic-liver-cancer-bclc-staging-and-classification The most commonly used is the Barcelona Clinic Liver Cancer system Early stage (A) asymptomatic patients with tumors appropriate for radical therapies Intermediate stage (B) asymptomatic patients with multi-nodular hepatocellular carcinoma may benefit from chemoembolization Barcelona Clinic Liver Cancer system advanced stage (C) symptomatic patient with vascular invasion, and/or extra-hepatic spread with preserved liver function could be treated with chemotherapy Barcelona Clinic Liver Cancer system terminal stage (D) disease should be offered systemic palliative therapy.  Liver cancer Evaluation Laboratory testing will help to evaluate the severity of liver disease including hypoalbuminemia, hyperbilirubinemia, and hypoprothrombinemia with the clinical inclusion of ascites and encephalopathy to classify according to the Child-Pugh assessment scale Imaging frequently identifies high-risk patients and is further characterized by dynamic contrasted-enhanced magnetic resonance imaging (MRI) or four-phase computer tomography (CT) Liver Biopsy Liver biopsy is not routinely done for HCC as the procedure is associated with the risk of tumor seeding and bleeding, and false negative on failure to obtain tissue from the appropriate site Serum Alpha-Fetoprotein (AFP) Alpha-fetoprotein is a serum glycoprotein produced by the fetal yolk sac and fetal liver during gestation. Elevated serum levels of AFP are typical for advanced HCC https://www.sgihealth.com/patients/digestive-health-library/liver-biopsy/  Liver cancer Treatment Surgical Resection Patients with Child–Turcotte–Pugh A and without clinically significant portal hypertension have favorable surgical resection outcomes Liver Transplantation Liver transplantation is associated with the removal of tumors and the potential for cure Tumor Ablation Patients with BCLC classification of very early (0) and early-stage (A) who do not meet surgical resection criteria are appropriate for ablation Ablation is by modifying the local tumor temperature by using either radiofrequency ablation (RFA), cryotherapy, microwave, or laser therapy or injection of chemical substances, including ethanol, boiling saline, and acetic acid Transarterial Therapies Transarterial chemoembolization (TACE) is the intraarterial infusion of cytotoxic agents and subsequent embolization of the feeding artery to the tumor Systemic Chemotherapy Sorafenib is the first-line treatment for the patient with BCLC advanced stage (C) with preserved liver function Other second-line medications include cabozantinib, ramucirumab, and nivolumab, which is a programmed cell death 1 (PD-1) immune checkpoint inhibitor Colon cancer  Colon cancer Colon cancer could present as Sporadic (70%) Familial clustering (20%) Inherited syndromes (10%) The transformation of the normal colonic epithelium to a precancerous lesion (adenoma) and ultimately to invasive carcinoma requires an accumulation of genetic mutations either somatic (acquired) and/or germline (inherited) Schmitt, M., Greten, F.R. The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol 21, 653–667 (2021). https://doi.org/10.1038/s41577-021-00534-x Colon cancer https://calgaryguide.ucalgary.ca/colorectal-carcinoma- pathogenesis-and-clinical-findings/  Colon cancer https://www.consultant360.com/articles/screening-staging-and-assessment-colorectal-cancer-cautionary-case https://www.chemoexperts.com/colon-cancer.html  Colon cancer Initial evaluation CT colonography (Colonoscopy sensitivity is about 94.7%) Tissue biopsy Routine laboratory workup with complete blood count, iron studies, basic metabolic panel, liver function test and coagulation tests are not diagnostic but often useful CEA greater than 5 ng/mL has a poor prognostic value when present  Oncofetal: Carcinoembryonic Antigen (CEA) Elevated Results found in Cancer Colorectal cancers ** Breast, lung, gastric, pancreatic, bladder, kidney, thyroid, head & neck, cervical, ovarian, liver, lymphoma, melanoma Non-Cancerous Reasons Cigarette smoking pancreatitis, hepatitis peptic ulcer disease hypothyroidism cirrhosis biliary obstruction  Colon cancer Treatment Endoscopic Resection Local excisions by endoscopy should achieve complete tumor resection and adjacent tissue in one block Surgical Resection The main goal for invasive Cca is the complete resection of the tumor and potential lymphovascular spread by a goal of a minimal negative proximal and distal margin of 5 cm for colon cancer, and minimal proximal margin of 5 cm and distal of 2 cm for rectal carcinoma Adjuvant chemotherapy There is no role for adjuvant chemotherapy for patients with Cca stage I. Low-risk stage II Cca patients can opt for surveillance without adjuvant therapy, individualized discussion with medical oncology or enrolled in a clinical trial Systemic Therapy More than half of all CRC patients will develop metastasis and the majority to the liver (80% to 90%) Current availability of nine different antineoplastic classes and more than a dozen drug options fluoropyrimidines (FU), capecitabine (CAP), S-1, tegafur plus uracil (UFT), irinotecan, oxaliplatin, anti-EGFRs (cetuximab, panitumumab), anti-VEGFRs (bevacizumab, ramucirumab), recombinant fusion protein (aflibercept), tyrosine kinase inhibitors (regorafenib), antimetabolites (TAS-102), immunotherapy (nivolumab, pembrolizumab) Cervical cancer  Cervical cancer Cervical cancer the fourth most common cancer among women worldwide, is caused almost entirely by human papillomavirus (HPV) High-risk types of HPV can lead to cervical intraepithelial lesions which, over time, can progress to cervical cancer Akram Husain RS, Ramakrishnan V (2016) A review of risk factors in the development of cervical malignancy. Cancer Sci Res Open Access 3(1): 1-4. DOI: http://dx.doi.org/10.15226/csroa.2016.00123  Cervical cancer Pathogenesis of cervical cancer. Epithelial cells in the transformation zone of the cervix acquire lesions upon persistent infection with high risk HPV (hrHPV). In some cases, the lesions resolve, whereas in others, upon viral integration, cells are transformed and progress from cervical intraepithelial neoplasia I to II and III (CIN1, CIN2, and CIN3). Viral proteins E6 and E7 are released and inhibit apoptosis mediated by TP53, cell cycle checkpoint by p21, T-cell response by toll-like receptors (TLR), and macrophage activation by cytokines. This leads to an insufficient immune response and viral replication, uncontrolled cell proliferation and genome instability, and further cancer in situ (CIS) or invasive cervical cancer (CC). Ramachandran, D.; Dörk, T. Genomic Risk Factors for Cervical Cancer. Cancers 2021, 13, 5137.  Cervical cancer Mustafa, Wan & Abd Halim, Afiqah & Jamlos, Mohd & Syed Idrus, Syed Zulkarnain. (2020). A Review: Pap Smear Analysis Based on Image Processing Approach. Journal of Physics: Conference Series. 1529. 022080. 10.1088/1742-6596/1529/2/022080.  Cervical cancer Algorithm for screening and treatment of cervical cancer Early warning signs of cervical cancer vaginal bleeding: between periods, after sexual intercourse or post-menopausal bleeding; unusual vaginal discharge, which may be watery, pink or foul-smelling pelvic pain Áyen, Á.; Jiménez Martínez, Y.; Boulaiz, H. Targeted Gene Delivery Therapies for Cervical Cancer. Cancers 2020, 12, 1301.  Cervical cancer Pap test A Pap smear can detect certain viral infections such as human papillomavirus (HPV), which is known to cause cervical cancer  Cervical cancer Vaccinate: key component of the comprehensive prevention and control strategy Two safe, effective vaccines that prevent infections from high-risk HPV types 16 and 18 are presently licensed in most countries One of the HPV vaccines (quadri- and nono-valent), also prevents infections from HPV types 6 and 11, which cause 90% of anogenital warts Vaccines do not cover all cancer-causing HPV types and do not treat pre-existing infections; thus, ongoing screening is mandatory Assignment Each students submit one page summary; 1) Epidemiology of cancer 2) Risk factor and Etiology to cancer 3) pathophysiology of cancer 4) Carcinogenesis, tumor grading, and staging 5) Test and Tumor marker for cancer diagnostic 6) Treatment cancer Submit the assignment on eLearning by FEB 28th, 2024 Overdue submissions will not be considered References Sansnee Senawong, Tumour marker, Siriraj E-public library Carolyn Vachani RN, MSN, AOCN, Patient Guide to Tumor Markers, All content © 2020 Trustees of the University of Pennsylvania. All rights reserved. National Institutes of Health|National Cancer Institute How Cancer Is Diagnosed - National Cancer Institute