Neoplasia Pathology

Question 1

Neoplasm

Answer 1

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

Question 2

Characteristics of benign and malignant

Answer 2

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

Question 3

Metaplasia

Answer 3

Reversible replacement of one cell type with another

Columnar to squamous is most common

Question 4

Dysplasia

Answer 4

Uniformity loss and architectural orientation loss

Question 5

Spread

Answer 5

Peritoneal cavity
Seeding
Lymphatic spread
Haematogenous spread

Question 6

Hypertrophy

Answer 6

Increased production of cellular proteins

Question 7

Atrophy

Answer 7

Reduction in cell size and number

Increased protein synthesis and increased protein degradation by ubiquitin proteasomes pathway

Question 8

Molecular basis

Answer 8

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

Question 9

Hallmarks of cancer

Answer 9

Self sufficiency
Insensitivity
Evasion of apoptosis
Altered cellular metabolism
Limitless replication potential
Sustained angiogenesis
Invasion and metastasis
Evade host immune response

Question 10

Oncogenes and proteins

Answer 10

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

Question 11

Cyclinns and CDK

Answer 11

G1/S transition most important in cancer —> gain of function and loss of function that stop inhibition of progression
G2M transition also important

Question 12

Tumour suppressor

Answer 12

Usually put breaks on DNA replication

Some also alter cell metabolism or ensure genomic stability

Question 13

P53

Answer 13

Induces cell cycle arrest
Induced senescence
Induced apoptosis

Inactivated by viral oncoproteins

Question 14

Metastatic cascade

Answer 14

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

Question 15

Immortality of cancer cells

Answer 15

Evasion of senescence
Evasion of mitotic crisis
Capacity for self-renewal

Question 16

Chemical carcinogenesis

Answer 16

Invitation

Promoters —> proliferation of initiated cells

Question 17

Radiation carcinogenesis

Answer 17

UV rays 280-320nm

Question 18

Microbial/virus carcinogenesis

Answer 18

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

Question 19

Grading and staging

Answer 19

Grading - degree of differentaiation

Staging - size and extent of spread

Question 20

Molecular basis of multi step carcinogenesis

Answer 20

NO single mutation
Malignant tumours result from stepwise accumulation of multiple mutations that act in complementary ways to produce a fully malignant tumour

Question 21

Cancer enabling inflammation

Answer 21

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

Question 22

Epigenetic changes

Answer 22

Histone modifications
DNA methylation
Other less well characterised proteins

Silencing of tumour suppressor genes
Global changes in DNA methylation
Changes in histones

Question 23

Seeding

Answer 23

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.

Question 24

Autosomal dominant syndromes

Answer 24

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.

Question 25

Direct acting carcinogens

Answer 25

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.

Question 26

Prostate cancer

Answer 26

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.

Question 27

Cyclins

Answer 27

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.

Question 28

Paraneoplastic

Answer 28

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.

Question 29

Gene mutations

Answer 29

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.