Neoplasia Pathology Flashcards
Neoplasm
Abnormal mass of tissue which growth exceeds normal tissue but persists in same excessive manner after cessation of stimuli which evoked the change
Series of acquired mutations affecting a single cell and its clonal progeny
Independent of physiologic growth signals
Neoplastic cells
Reactive stroma
Adenoma - derived from glands epithelial
Papilloma - epithelial finger like projections
Malignant - sarcoma - solid mesenchymal tissue
Leukaemia - blood
Lymphoma - lymphocytes
Carcinoma - epithelial cell origin from any germ cell layer
Pleomorphic adenoma - both epithelial and myoepithelial cells
Teratoma - belongs to more than one germ cell layer - ovary and testis (from totipotential germ cell Ellis)
Hamartoma - benign cells indigenous to involved site
Characteristics of benign and malignant
Differentiation - well compared to poor
Anaplastic cells - new unanticipated functions - paraneoplastic syndromes
Pleomorphis - variation in size and shape
Abnormal nuclear morphology - large nuclei
Mitosis - - bizzare moitotic figures
Loss of polarity
Other changes - e.g. ischaemic necrosis
Degree of metaplasia and dysplasia
Local invasion - benign usually form a capsule and well demarcated vs not
Metastasis means malignant
Metaplasia
Reversible replacement of one cell type with another
Columnar to squamous is most common
Dysplasia
Uniformity loss and architectural orientation loss
Spread
Peritoneal cavity
Seeding
Lymphatic spread
Haematogenous spread
Hypertrophy
Increased production of cellular proteins
Atrophy
Reduction in cell size and number
Increased protein synthesis and increased protein degradation by ubiquitin proteasomes pathway
Molecular basis
Non lethal genetic damage
Mutations in protooncogenes
Tumour suppressor - recessive
Apoptosis regulating genes
DNA repair genes
Accumulation of complemetary mutations over time in step wise fashion
Driver mutations, no single mutation is transformatory
Loss of function mutations are a common early step
Passenger mutations have no phenotypic consequence and are much more common - no advantage to tumour cell
10 to the 9 requires 30 cell doubling and represents 1cm in diameter
Epigenetic alteranations like DNA methylation and his tone modification also contribute - epigenetic changes are potentially reversible by drugs that inhibit DNA or his tone modifying factors
Hallmarks of cancer
Self sufficiency Insensitivity Evasion of apoptosis Altered cellular metabolism Limitless replication potential Sustained angiogenesis Invasion and metastasis Evade host immune response
Oncogenes and proteins
Promote autonomous cell growth in cancer cells and unmutated cellular counterparts are called proto oncogenes
Proteins called onto proteins are encoded
Proto drive signalling pathways that drive proliferation
ONCOPROTEINS are consitututively active compared with protooncogenes
Tyrosine kinase pathway, etc abnormalities in these pathways usually implicated but tyrosine kinase most frequently mutated one
Tumour suppressors antagonise oncoproteins
Cyclinns and CDK
G1/S transition most important in cancer —> gain of function and loss of function that stop inhibition of progression
G2M transition also important
Tumour suppressor
Usually put breaks on DNA replication
Some also alter cell metabolism or ensure genomic stability
P53
Induces cell cycle arrest
Induced senescence
Induced apoptosis
Inactivated by viral oncoproteins
Metastatic cascade
Invasion of ECM, Vascular dissemination, homing of tumour cells and colonisation
Dissociation of cancer cells, Degradation of basement membrane and interstitial connective tissue, Changes in attachment of tumour cells to ECM proteins, Locomotion (degraded basement membrane)
CLONAL EXPANSION —> METASTATIC SUBCLONE —> ADHESION BASEMENT MEMBRANE —> ECM —> INTRAVASATION —> HOST LYMPOHOID CELLS —-> TUMOUR CELL EMBOLUS —> Adhestion basement membrane —> EZXTRAVASATION —> Metastatic deposit —> ANGIOGENSIS
Immortality of cancer cells
Evasion of senescence
Evasion of mitotic crisis
Capacity for self-renewal
Chemical carcinogenesis
Invitation
Promoters —> proliferation of initiated cells
Radiation carcinogenesis
UV rays 280-320nm
Microbial/virus carcinogenesis
HTLV1 - T cell lymphoma
HPV - Cervical, anogenital, head and neck
EBV - B cell lymphomas, Burkett lymphoma, nasopharyngeal and gastric cancer
HepB and Hep C - hepatocellular carcinoma
Merkel Cell Polyoma virus
Kaposi sarcoma herpesvirus
H pylori
Grading and staging
Grading - degree of differentaiation
Staging - size and extent of spread
Molecular basis of multi step carcinogenesis
NO single mutation
Malignant tumours result from stepwise accumulation of multiple mutations that act in complementary ways to produce a fully malignant tumour
Cancer enabling inflammation
Anaemia, fatigue, cache is
Release of growth tractors and proteases from infiltrating leucocytes and activated stromal cells
Enhanced resistance to cell death
induce angiogenesis
Invasion and metastasis
Epigenetic changes
Histone modifications
DNA methylation
Other less well characterised proteins
Silencing of tumour suppressor genes
Global changes in DNA methylation
Changes in histones
Seeding
Tumour spread by seeding is common in malignant tumours that invade a natural body cavity. This is particularly characteristic of ovarian cancer, ependymoma, and medulloblastoma. Ovarian cancer is widely covered by the peritoneum, and therefore it can invade and spread throughout the peritoneal cavity. This is known as “transcoelomic spread”. Ependymoma and medulloblastoma can invade the ventricular cavities of the brain and spread along the meninges in the brain and spinal cord. Primary CNS lymphoma is characterised by local invasion rather than metastasis or seeding, and leukaemia is a disseminated malignancy of blood components.
Autosomal dominant syndromes
Some examples of autosomal dominant cancer syndromes are retinoblastoma, Li–Fraumeni syndrome, neurofibromatosis 1 and 2, hereditary non-polyposis colorectal cancer (HNPCC), and multiple endocrine neoplasias. Individuals with a dominant mutation have a high risk of transmitting the mutated gene to their offspring, which greatly increases the risk of malignancies in subsequent generations. Some examples of autosomal recessive syndromes are Fanconi anemia, ataxia-telangiectasia, Bloom syndrome, and xeroderma pigmentosum.
Direct acting carcinogens
Direct-acting carcinogens require no metabolic activation before being carcinogenic. They are divided into alkylating and acylating agents. Some examples of alkylating agents include dimethyl sulfate and diepoxybutane. An example of an acylating agent is I-Acetylimidazole. Benzo(a)pyrene is a pro-carcinogen that needs to be metabolically activated before being carcinogenic. Aflatoxin B1 is a plant-based carcinogen.
Prostate cancer
Men chronically exposed to cadmium and cadmium compounds are at high risk of developing prostate cancer. Cadmium is used in yellow pigments, phosphors, solders, batteries, as alloy, and in metal plating and coatings. Benzene increases the risk for acute myeloid leukaemia. Asbestos increases the risk for mesothelioma, as well as lung, oesophageal, gastric and colon cancers. Vinyl chloride increases the risk for hepatic angiosarcoma, and chromium increases the risk for lung cancer.
Cyclins
Cyclins bind to cyclin-dependent kinases and control orderly progression through the cell cycle, usually by phosphorylating key proteins involved in this process. Different cyclins are involved with each step of the cell cycle. Overexpression of cyclin D is seen in many cancers; mutations of cyclin-dependent kinase 4 are seen in melanomas and sarcomas.
p53 is a tumour suppressor gene found on chromosome 17. It detects DNA damage and can activate DNA repair proteins, halt the cell cycle, or initiate apoptosis. Mutations will inactivate these functions, and allow a faulty cell to continue through the cell cycle. It is the most commonly mutated gene in human cancers.
p21 is a gene coding for a cyclin-dependent kinase inhibitor. This protein arrests the cell cycle at the transition from G1 to S phase; it is induced by p53. Mutations will remove this check on progression through the cell cycle.
Paraneoplastic
Paraneoplastic syndromes are constellations of signs and symptoms that cannot be directly explained by the local effects of a tumour. They are seen in around 10% of individuals with cancer. The most common of these is hypercalcaemia. Many of the paraneoplastic syndromes are due to hormone or hormone-like substance production, but others arise due to poorly-understood mechanisms, including myasthenia and hypertrophic pulmonary osteoarthropathy in association with bronchogenic carcinoma.
Thymomas are found in around 20% of patients with myasthenia gravis. Other autoimmune associations include red cell aplasia and thymoma-associated multiorgan autoimmunity. One-third of patients with thymoma present with an autoimmune condition, one-third with local compressive symptoms (e.g. superior vena cava obstruction), and one-third are asymptomatic. They may be benign or, rarely, malignant. Surgery is usually curative.
Carcinoid syndrome is associated with carcinoid tumours of the midgut. They are sometimes found in the lung. Carcinoids in the liver are usually metastases. Most carcinoids are asymptomatic, but 10% are associated with the syndrome of flushing, diarrhoea, wheeze, abdominal crampy pain and oedema. This is due predominantly to hypersecretion of serotonin.
Cushing syndrome results from excessive secretion (or, most commonly, ingestion) of cortisol. Pituitary and adrenal gland tumours and small cell lung cancer are associated.
SIADH (syndrome of inappropriate antidiuretic hormone secretion) results in renal retention of water and may result in hyponatraemia. Causes are multiple, but include CNS pathology (Guillain–Barre, meningitis, haemorrhage, trauma), ADH-secreting tumours (lung, gastrointestinal, urothelial), benign lung disease (pneumonia, lung abscess, sarcoidosis, cystic fibrosis), and many drugs.
Polycythaemia results from excess red blood cell production, or erythropoietin (EPO) secretion in response to tissue hypoxia, for example in smokers. Some tumours, such as renal cell carcinomas, produce EPO.
Gene mutations
Multiple endocrine neoplasia 1 (MEN 1) and multiple endocrine neoplasia 2 (MEN 2) are caused by mutations in the genes MEN1 and RET, respectively. Bloom syndrome and neurofibromatosis type 1 are caused by mutations in the genes BLM and NF1, respectively. Xeroderma pigmentosum is caused by mutations in various genes involved in nucleotide excision repair.
