tumour pathology Flashcards
what is a neoplasm
A neoplasm is an abnormal mass of tissue , the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in same excessive manner after cessation of the stimuli which evoked change.
Abnormal mass is purposeless, preys on the host and virtually autonomous.
Two fundamental features of neoplasm are unregulated growth and clonal genetic defects (derived from single cell and all the cells in the neoplasm are clonal related)
metastasis
spread to distant, non-contiguous site
Lymphatic metastasis (spread to lymph nodes)
Haematogenous metastasis (spread to lung, liver, bone, brain, etc)
Implantation in body cavities (Pleural and peritoneal metastasis)
benign neoplasms
Cohesive, expansile, well demarcated masses, do not invade or infiltrate surrounding normal tissue (can push local structures, put pressure on them but do not invade)
Usually progressive and slow growth (can be seen on clinical and radiological examination); may come to a standstill or regress; mitotic figures rare and normal - some benign tumours have higher growth rates than malignant tumours
Well differentiated; structure sometimes typical of tissue of origin
Do not metastasize
malignant neoplasms
Locally invasive, infiltrating surrounding tissue; sometimes may be misleadingly cohesive and expansile
Infiltrative borders - stellate, spiculated (Can be seen on radiological and histopathological examination).
Locally advanced malignant tumours are fixed to adjacent structures and not mobile. (Clinical examination – palpation of the tumour)
May grow slowly or rapidly; mitotic figures may be numerous and abnormal
Some lack of differentiation (anaplasia); structure often atypical
Metastasis - Frequent; more likely with large undifferentiated primary tumours
anaplasia
anaplasia- lack of differentiation
Abnormal nuclei - high nucleus to cytoplasmic ratio, hyperchromatic nuclei (due to replicating DNA), clumped chromatin, prominent nucleoli
Anaplastic nuclei may have multiple copies of chromosomes and therefore more DNA
pleomorphism
variation in size and shape of cells and nuclei, abnormal mitotic figures
benign epithelial neoplasms
Adenoma - derived from glandular epithelium
Cystadenoma - benign epithelial neoplasm with cystic or fluid filled cavity
Papilloma - benign epithelial neoplasm producing finger like projections
benign mesenchymal neoplasms
Fat – Lipoma Smooth muscle – Leiomyoma Skeletal muscle – Rhabdomyoma Cartilage – Chondroma Bone – Osteoma Blood vessels – Haemangioma Fibrous tissue - Fibroma
malignant neoplasms (nomenclature)
Carcinoma - arising from epithelial tissue
Adenocarcinoma - arising from glandular epithelium
Squamous cell carcinoma – arising from squamous epithelium
Small cell carcinoma – arising from neuroendocrine cells or pleuripotent stem cells
Melanoma – arising from melanocytes
Sarcoma - arising from mesenchymal tissue
Lymphoma - arising from lymphoid tissue
Leukaemia - arising from blood or bone marrow elements
definitions: mixed tumours, teratomas, blastomas
- Neoplasms with more than one cell type but arising from only one germ layer are called ‘mixed tumours’
- Neoplasms with more than one cell type and arising from more than one germ layer are called teratomas
- Neoplasms ending in ‘blastoma’ resemble primitive embryonic tissues, which are often paediatric neoplasms (e.g. Retinoblastoma, Neuroblastoma)
what is tumour grade?
Histologic parameter quantifying degree of differentiation
Well differentiated (low grade) tumours resemble mature normal cells of the tissue of origin
Poorly differentiated (high grade) tumours show little resemblance to tissue of origin
Limitations - Many tumours show intermediate differentiation, sampling error in small biopsies, interobserver variation for assessment of grade (subjective light microscopic interpretation)
what is tumour stage?
AJCC and UICC (TNM)
Size of the tumour, extent of invasion, lymph node involvement, distant metastasis
Important in planning appropriate treatment, prognosis, research and guidelines
what are the clinical manifestations of cancer?
Cancer can cause illness by Local invasion and impingement on local structures Ulceration, bleeding and infection Cachexia Paraneoplastic process
causes of neoplasia
Environmental causes – Chemicals, Oncogenic viruses, Radiation
Hereditary causes
carcinogen
An external agent that increases the incidence of malignant neoplasms, reduces their latency, or increases their severity or multiplicity – WHO
chemical carcinogens
- There are two steps: initiation and promotion
- An initiating carcinogenic agent irreversibly damages cell DNA (it is mutagenic) to start the process
- A promoting agent (which may be the same as the carcinogen) then acts (reversibly) to cause proliferation of a neoplastic cell clone, but there appears to be a “dose-threshold” concentration of promoter below which neoplasia will not occur.
Many chemical carcinogens are highly reactive electrophiles (have electron deficient atoms) that can react with nucleophilic (electron rich) sites in the cell, including DNA, RNA and protein. Direct carcinogens (direct acting alkylating agents) Indirect carcinogens (aka procarcinogens) - Metabolite is the active carcinogen
types of procarcinogens
Polycyclic aromatic hydrocarbons: the most potent carcinogen, produced in combustion of tobacco, can cause lung and bladder cancers
Tobacco smoke contains over 4000 chemical compounds
Aromatic amines (in dye and rubber) and azo dye (food colour)
Naturally occurring carcinogens: aflatoxin B in stored peanuts and grains, cause liver cancer
Nitrosamines and amides: nitrate preservatives are converted by bacteria in gastrointestinal tract and may contribute to gastric cancer
metabolic activation of procarcinogens
Most known carcinogens are metabolized and activated by cytochrome P-450 dependent mono- oxygenases
A P-450 gene product, CYP1A1 metabolize polycyclic aromatic hydrocarbons
Cytochrome P-450 enzymes are polymorphic
A highly inducible form of CYP1A1 is associated with higher risk to develop lung cancer in smokers.
Inactivation of procarcinogen or its derivatives
Glutathione-S-transferase (GST) inactivates polycyclic aromatic hydrocarbons
GST is deleted in many patients, who incur a higher risk of lung and bladder cancer if exposed to tobacco smoke.
occupational cancer
Examples of occupational cancers Arsenic (metal smelting, herbicide) lung and skin cancers Asbestos (fire-resistant textile, brake lining, tiles) lung, mesothelioma and GI tract cancers Benzene (light oil, paint, dry cleaning) leukaemia, Hodgkin lymphoma Vinyl chloride (refrigerant and plastics) Angiosarcoma and liver cancer
radiation
• Ultraviolet light
Skin cancers
• Ionizing radiation (X-rays, gamma rays)
Leukaemia, thyroid, breast and many others
infectious agent carcinoma
Viruses:
Human papilloma virus (HPV) – Cervical cancer
Epstein-Barr Virus (EBV) – Lymphoma, Nasopharyngeal carcinoma
Hepatitis B and C viruses – Liver Cancer
Human T-cell lymphotrophic virus-1– Leukaemia/lymphoma
Bacteria:
Helicobacter Pylori – Stomach Cancer (Lymphoma and carcinoma)
Parasites:
Shcistosoma haematobium–Bladder Cancer
Opisthorchis viverrini– Bile duct cancer
dietary carcinogens
Aflatoxins (product of mould on peanuts, etc)
Liver cancer
Arsenic
Lung and skin cancer
therapeutic carcinogens
- Many chemotherapy agents (lymphomas and leukemias).
* Estrogenic hormones (endometrium, breast).
cultural and lifestyle habits
Tobacco smoke – Lung and respiratory tract, kidney, bladder, and pancreas cancers
Ethanol – Liver, upper aerodigestive tract cancers
Betel quid – Mouth cancer
Smokeless tobacco – Mouth cancer
Obesity - Colon, endometrial, breast cancer
inherited cancer syndromes - autosomal dominant
Autosomal Dominant
Inheritance of a mutated allele of a single tumour suppressor gene increases the risk of cancer
Retinoblastoma: Rb Li-Fraumeni syndrome: p53 Neurofibromatosis 1 and 2: NF1, NF2 Melanoma: p16INK4A Breast and Ovarian: BRCA1,BRCA2 Multiple endocrine neoplasia 1 and 2: MEN1, RET Basal cell carcinoma: PATCH Familial adenomatous polyposis (FAP): APC
inherited cancer syndromes- autosomal recessive
Mostly defects in DNA repair • Xeroderma Pigmentosum • Ataxia-telangiectasia • Bloom Syndrome • Fanconi Anaemia
unclassified familial clusters
Virtually all common cancers have familial forms that are not well defined
Cancers in multiple close relatives
Multiple cancers in individuals
Persistence over several generations
Most have unclear (?multigene?) inheritance patterns
Many more genetic causes of familial cancer remain to be discovered!
High rate of cancer within family, but unclear mechanism of inheritance, and no genetic defect identified
defective DNA repair syndromes
Defect in DNA repair and resultant DNA instability
e.g. Lynch syndrome, Xeroderma pigmentosum
cellular transformation
There are “pre-cancerous” conditions in which malignant neoplasia is more likely to occur (but not in every case): liver cirrhosis, chronic ulcerative colitis, atrophic gastritis, epidermal actinic keratosis, and oral leukoplakia. In these cases, there is ongoing cellular proliferation for repair of damaged tissue, often from ongoing inflammation. Abnormal cell proliferation leads to a greater likelihood for mutation to occur.
hyperplasia
An increase in the number of cells in an organ or tissue, which may then have increased volume.
Physiologic hyperplasia – e.g. Postpartum breast lobules undergo hyperplasia for lactation
Pathologic hyperplasia – e.g. Endometrial hyperplasia in a postmenopausal woman – Fertile soil in which cancerous proliferation may arise
metaplasia
Metaplasia is a reversible change in which one adult cell type is replaced by another adult cell type
e.g. Columnar to squamous in respiratory tract due to chronic irritation
Squamous to columnar in Barrett’s oesophagus
dysplasia
An increasing degree of disordered growth or maturation of the tissue (often thought to precede neoplasia) such as cervical dysplasia as a result of human papillomavirus infection. Dysplasia is still a reversible process. However, once the transformation to neoplasia has been made, the process is not reversible.
characteristics of cancer
- sustaining proliferative signalling
- avoiding immune destruction
- evading immune suppressors
- enabling replicative immortality
- tumour-promoting inflammation
- activation invasion and metastasis
- genomic instability (mutator phenotype)
- inducing angiogenesis
- resisting cell death
- deregulating cellular energetics
activation of Non- Receptor Kinases
1) BCR-ABL translocation in Chronic myeloid leukaemia
- bcr-abl fusion protein has sustained tyrosine kinase activity
- derives CML: oncogene addiction
- Gleevac inhibits TK activity
2) JAK-2 Mutations
- sustained activation of the STAT signalling pathway
- occurs in chronic myoproliferative disorders
- > Polycythemia vera
- > primary myelofibrosis
mutational activation of nuclear transcription factors
- drive the cell cycle in the absence of any growth promoting signals
- MYC most commonly involved
- mutant MYC upregulates Cyclin-depent kinases CDKs and inhibits their inhibitors (CDKIs)
- mutant MYC promotes aerobic glycosylation (Warburg effect)
Rb gene
RB is a tumour suppressor gene, it monitors G1-s checkpoint.
hypophosphorylated Rb sequester E2F and prevents transcription of genes required for DNA synthesis such as cyclin E
tumour suppressor gene
prevents cell growth/division
loss of function
car brakes
two hits
proto-oncogenes/oncogenes
promotes cell growth/division
gain of function
car accelerator
one hit
enabling replicative immortality
- tumour cells use an enzyme called telomerase which adds telomeres onto the end of chromosomes
- cell can now divide indefinitely without entering senescence
tumour promoting inflammation
- many tumours are infiltrated with leukocytes of all types
- these may be manifestations of host responses to tumours
- it seems that inflammatory cells may promote tumour growth
- > secretion of EGF and VEGF
- > secretion of MMPs that digest the stroma and create planes for invasion
- > release free radicals- additional DNA damage
deregulating cellular energetics
- ’ aerobic glycolysis’
- tumour cells convert glucose -> lactate in the presence of oxygen
- less efficient than normal glycolysis
- increased expression of GLUT1 as compensation
- facilitates the biosynthesis of macromolecules (amino acid precursors) for formation of daughter cells
