Pathology Part 2 Knowt flashcard

Define cancer and explain its fundamental biological characteristics.

Cancer is not a single disease, but a broad group of diseases fundamentally characterised by uncontrolled cell growth, cell division, and the ability to spread (metastasise) throughout the body.

State the annual incidence and mortality burden of cancer in the UK.

In the UK, there are approximately 385,000 new cases and 167,000 cancer deaths annually. Breast, prostate, lung, and bowel cancers account for over 53% of new diagnoses and roughly 45% of deaths.

Why does cancer preferentially arise in certain tissues?

Cancer preferentially arises in tissues whose cells are actively dividing and frequently exposed to environmental damage (e.g., the epithelial linings of the colon and lungs).

Describe the changing demographics of cancer incidence.

Notably, there has been a recent shifting demographic, with incidence rates among people under 50 rising by 24% over the last two decades.

What proportion of cancers are considered preventable?

It is estimated that 38% of cancers are preventable through lifestyle modifications like smoking cessation.

List the phases of the cell cycle.

The cell cycle consists of resting (G0), preparation (G1), DNA synthesis (S), checking (G2), and division (M/Mitosis) phases.

Explain the role of cyclins and CDKs in cell-cycle regulation.

The cycle is strictly regulated by proteins called cyclins and Cyclin-Dependent Kinases (CDKs). Cyclins bind to CDKs to activate them, causing cascading phosphorylation that drives the cell cycle forward.

Why is the G1 to S checkpoint considered the most critical checkpoint?

The G1 to S checkpoint is the most critical decision point, assessing cell size, nutrients, and DNA damage. If damage is detected, CDK inhibitors halt the cycle.

Explain the “multiple hit” hypothesis of carcinogenesis.

It rarely takes just one mutation to cause cancer. Generally, a cell must accumulate an average of four to seven mutations in key regulatory genes to become malignant.

Define oncogenes and proto-oncogenes.

These genes promote cell growth and division. In a healthy cell, they are termed proto-oncogenes. When mutated, they become permanently activated, generating excessive signals for the cell to divide.

Give examples of important oncogenes and the cancers associated with them.

Examples: Ras (mutated in 90% of pancreatic cancers) and EGFR (overexpressed in glioblastomas).

Describe the function of tumour-suppressor genes.

These genes inhibit cell division and induce apoptosis (programmed cell death) if a cell is damaged. Mutations inactivate these genes, removing the cell's safety brakes.

Why is p53 referred to as the “guardian of the genome”?

p53 (the "guardian of the genome," mutated in >50% of human cancers).

Describe the role of DNA repair genes in preventing malignancy.

These genes fix spontaneous DNA damage. When they are mutated, the cell cannot efficiently repair its genome, leading to the rapid accumulation of further mutations.

Explain the role of BRCA1 and BRCA2.

BRCA1 & BRCA2 normally repair DNA double-strand breaks.

Explain how cancer cells achieve immortality.

Normal somatic cells have a lifespan (the Hayflick limit of ~40-60 divisions) dictated by the shortening of telomeres at the ends of their chromosomes. Cancer cells evade this by overexpressing the enzyme telomerase, which continuously lengthens the telomeres, granting them cellular immortality.

Why is angiogenesis essential for tumour survival?

Tumours cannot grow beyond a certain size without a dedicated blood supply for oxygen, nutrients, and waste removal. They secrete Vascular Endothelial Growth Factor (VEGF) to attract and sprout new blood vessels from existing capillaries.

Explain the tumour microenvironment (TME).

Cancer is not just a ball of mutated cells; it is a complex environment. It hijacks fibroblasts to remodel the extracellular matrix (ECM) and recruits macrophages to suppress the host's immune system.

Define the Warburg Effect.

Metabolically, cancer cells undergo the Warburg Effect—shifting to rapid glucose uptake and high lactate production (glycolysis) even in the presence of oxygen. This creates a hypoxic, acidic environment that resists medications and aids tissue breakdown for invasion.

How do Matrix Metalloproteinases (MMPs) facilitate metastasis?

For a cancer to spread, it must first detach from its neighbouring cells and degrade the surrounding ECM using enzymes called Matrix Metalloproteinases (MMPs).

Outline the stages of the metastatic cascade.

1. Intravasation: Squeezing into blood or lymphatic vessels. 2. Circulation: Travelling the body whilst evading immune surveillance. 3. Extravasation: Exiting the vessels into distant tissue. 4. Colonisation: Adapting to a new environment and establishing a secondary tumour.

How do cancer cells evade the immune system?

Cancer cells mask themselves by downregulating cell-surface proteins and producing proteins that actively inhibit immune cell function.

Explain the principles of PET scanning in oncology.

PET scans use radioactive glucose, which highly metabolic cancer cells readily absorb.

Define carcinoma.

Carcinoma: A cancer arising from epithelial cells (the cells lining the skin, organs, and body cavities). The most common type of cancer globally.

Define adenocarcinoma.

Adenocarcinoma: A subtype of carcinoma arising specifically from glandular epithelial tissue.

Define sarcoma.

Sarcoma: A cancer arising from connective tissues, such as bones, muscles, and soft tissues.

Define metastatic organotropism.

Metastatic Organotropism: The phenomenon where circulating cancer cells preferentially colonise specific distant organs because those environments are biologically similar or hospitable to the original cell type (e.g., breast cancer preferentially metastasising to bone, liver, and lungs).

What are RECIST criteria?

RECIST Criteria: (Response Evaluation Criteria in Solid Tumors) - The clinical standard used to measure if a solid tumour is shrinking in response to therapy.

Differentiate NSCLC and SCLC.

Lung cancer is predominantly divided into Non-Small Cell Lung Cancer (NSCLC) (85% of cases) and Small Cell Lung Cancer (SCLC).

Describe adenocarcinoma of the lung.

NSCLC - Adenocarcinoma: The most common overall, typically found in the outer alveolar glands. Notably, this is the most common lung cancer found in non-smokers.

Describe squamous cell carcinoma of the lung.

NSCLC - Squamous Cell Carcinoma: Begins in the central bronchi and is almost exclusively associated with smoking.

Why is SCLC considered highly aggressive?

SCLC: Extremely aggressive, composed of tiny cells that rapidly metastasise to other areas of the body early in the disease progression.

What environmental factors contribute to lung cancer in non-smokers?

Environmental exposure to radon gas in homes, air pollution, and occupational asbestos are critical aetiological factors, particularly for non-smokers.

Why is lung cancer prognosis poor?

Because the lungs are large, air-filled cavities, tumours can grow for a long time without compressing vital structures. Symptoms (persistent cough, weight loss, coughing up blood) present very late. Consequently, the prognosis is exceptionally poor, with less than 10% of patients surviving beyond 10 years.

Explain the Philadelphia chromosome and its significance.

A single chromosomal translocation between chromosomes 9 and 22 can fuse the BCR and ABL genes together. This creates an abnormally powerful oncogene that single-handedly drives the development of Chronic Myeloid Leukaemia (CML).

Why does cancer treatment require a multifaceted approach?

Treating cancer requires a multifaceted approach because every patient's cancer is genetically unique, and tumours frequently develop resistance to single therapies.

What are the primary pillars of cancer treatment?

The primary pillars of cancer treatment include: Traditional Modalities: Surgery, radiation therapy, and chemotherapy. Targeted Therapy: Using drugs to specifically target molecular changes driving the cancer. Immunotherapy: recruit the patient's own immune system to find and destroy hidden cancer cells.

Explain the principle of CAR T-cell therapy.

CAR T-Cell Therapy: Extracting a patient's immune cells, re-engineering them in a lab to easily find cancer cells, and returning them to the body.

Describe HPV structurally.

Human Papillomavirus (HPV), a non-enveloped, double-stranded DNA virus.

Which HPV strains are most strongly associated with cervical cancer?

The high-risk oncogenic subtypes HPV 16 and 18 are responsible for at least two-thirds (and up to 85% when combined with other high-risk strains) of all cervical cancer cases.

Explain the role of E6 in cervical carcinogenesis.

E6: Binds to and degrades the tumour suppressor protein p53. Without p53, the cell cannot undergo apoptosis (programmed cell death) if its DNA is damaged, and the expression of telomerase is upregulated.

Explain the role of E7 in cervical carcinogenesis.

E7: Binds to and degrades the Retinoblastoma protein (pRb). This removes the "brake" on the cell cycle, releasing E2F transcription factors which directly force the cell into the S-phase for uncontrolled DNA synthesis.

Outline the NHS cervical screening pathway.

The NHS screens women aged 25–64 (every 3 years until 49, then every 5 years). A brush collects cells from the cervix and deposits them in a liquid fixative. The sample is first tested for high-risk HPV (hrHPV). If positive for hrHPV, the same sample undergoes cytology to look for dyskaryosis. If cytology is abnormal, the patient is urgently referred for a colposcopy.

Explain how acetic acid identifies abnormal cervical tissue.

Acetic Acid: Dehydrates cells. Dysplastic (abnormal) cells lack glycogen and have high nuclear density, causing them to turn white (aceto-white).

Explain the principle of Lugol’s iodine staining.

Lugol’s Iodine: Normal cells are rich in glycogen and take up the iodine, staining brown/black. Abnormal cells lack glycogen, fail to stain, and appear pale or yellow.

Describe CIN 1.

CIN 1 (Mild Dysplasia): Abnormal cells confined to the lower 1/3 of the epithelium.

Describe CIN 2.

CIN 2 (Moderate Dysplasia): Abnormal cells affecting the lower 2/3 of the epithelium.

Describe CIN 3.

CIN 3 (Severe Dysplasia): Abnormal cells affecting the full thickness (>2/3) of the epithelium, but have not breached the basement membrane.

Define the transformation zone.

Transformation Zone: The anatomical area on the cervix where the stratified non-keratinised squamous cells of the ectocervix meet the tall mucinous columnar cells of the endocervix (the squamocolumnar junction). This is the primary site of HPV infection and carcinogenesis.

Differentiate dyskaryosis from dysplasia.

Dyskaryosis: A cytological term referring to the abnormal appearance of individual cell nuclei. Dysplasia: A histological term referring to the deranged architectural growth and disorganisation of tissue layers.

Define carcinoma in situ.

Carcinoma in situ: A pre-invasive stage where neoplastic cells occupy the full thickness of the epithelium but have not yet crossed the basement membrane to invade deeper tissues.

What is the LLETZ procedure?

LLETZ Procedure: Large Loop Excision of the Transformation Zone. A treatment where an electric current passes through a wire loop to shave away the abnormal cervical cells.

Explain the mechanism of Gardasil 9.

Gardasil 9: A recombinant Virus-Like Particle (VLP) vaccine given prophylactically to 12-13 year olds. It uses L1 capsid proteins to mimic the HPV virus shell, stimulating immunity against 9 HPV strains (including 16 and 18) without containing actual viral DNA.

What risk factors were identified in Sarah’s cervical cancer case?

Smoking (10-15 cigarettes/day), multiple sexual partners in her 20s, no HPV vaccination, and infrequent smears (none in the last 5 years).

Why did Sarah require chemoradiotherapy rather than surgery?

Further imaging (MRI/CT) reveals the tumour involves the upper 2/3 of the vagina with parametrial invasion, classifying it as FIGO Stage IIb1. Because it has spread beyond the cervix (Stage 2+), management requires chemotherapy and radiotherapy.

How should hrHPV-positive but cytology-negative patients be managed?

Abby is advised to return for a repeat screening in 12 months. If she tests positive for HPV three consecutive times, she will be referred to colposcopy regardless of whether her cytology remains normal.

Describe an endocervical polyp.

Endocervical Polyp (Benign): A fleshy growth protruding from the endocervical canal, lined with columnar epithelium and protected by mucus.

Describe a Nabothian cyst.

Nabothian Cyst/Follicle (Benign): A harmless, mucus-filled lump on the transformation zone, visually identifiable by a light reflection at its tip.

Describe cervicitis.

Cervicitis (Benign): Severe inflammation of the cervix, often characterized by a purulent exudate and easily induced bleeding upon contact.

State the functions of the femur in knee mechanics.

Femur: The large upper bone that supports the patella and provides shock absorption.

State the role of the tibia in the knee.

Tibia: The primary weight-bearing bone of the lower leg that forms the main joint with the femur.

State the role of the fibula.

Fibula: The smaller lateral bone of the lower leg, primarily involved in managing uneven weight distribution.

Explain the biomechanical role of the patella.

Patella (Kneecap): Acts as a pivot or pulley mechanism to enhance the power of the quadriceps during knee extension.

Describe the functions of the quadriceps.

Quadriceps: A massive four-muscle group on the anterior thigh responsible for knee extension (straightening) and preventing hyperflexion.

Describe the functions of the hamstrings.

Hamstrings: Located on the posterior thigh, responsible for knee flexion (bending) and preventing hyperextension.

Explain the function of cruciate ligaments.

The Anterior (ACL) and Posterior (PCL) cruciate ligaments prevent extreme forward/backward movements and hyperextension.

Explain the function of collateral ligaments.

The Medial (MCL) and Lateral (LCL) ligaments prevent the knee from buckling under inward (valgus) or outward (varus) lateral forces.

Why is cartilage vulnerable to degeneration?

Cartilage is avascular (lacks a direct blood supply) and relies entirely on the surrounding synovial fluid for nourishment.

State the functions of the meniscus.

Meniscus: Disc-like structures that act as the primary shock absorbers between the femur and tibia.

Describe articular cartilage.

Articular Cartilage: Coats the ends of the bones to provide smooth, frictionless movement (congruency).

Explain first-class lever systems.

First-Class Lever: The joint (fulcrum) is in the middle. Example: Neck extension.

Explain second-class lever systems.

Second-Class Lever: The load is in the middle. Example: Doing a calf raise on your tiptoes.

Explain third-class lever systems.

Third-Class Lever: The effort is in the middle. This is the most common lever in the body but the least mechanically efficient. Example: Knee or elbow flexion/extension.

Explain cartilage degradation in osteoarthritis.

Mechanical stress breaks down the proteoglycans and collagen in the articular cartilage. The synthesis of new cartilage by chondrocytes cannot keep pace with the degradation, leading to a loss of joint smoothness and increased friction.

Define subchondral sclerosis.

As cartilage is lost, the underlying subchondral bone thickens to compensate. This is known as subchondral sclerosis, which appears brightly white on an X-ray and can lead to microfractures.

What are osteophytes and why do they form?

The bone margins develop small bony projections (spurs) known as osteophytes in a desperate attempt to add stability and stiff restricted joint to limit painful movement. the body grows osteophytes around the edges of the joint to increase the surface area anhd distribute weight.

Explain inflammatory flares in OA.

The physical damage triggers the release of pro-inflammatory cytokines, activating COX-2 enzymes to produce prostaglandins. This causes acute pain flares, synovial swelling, and excess synovial fluid production.

Define valgus and varus forces.

Valgus refers to forces pushing the knee inward (knock-kneed), resisted by the MCL. Varus refers to forces pushing the knee outward (bow-legged), resisted by the LCL.

What are proteoglycans?

Proteoglycans: Highly glycosylated proteins that form a vital structural scaffolding in the extracellular matrix of cartilage.

Define cachexia.

Cachexia: Severe, unexplained muscle wasting and weight loss, frequently associated with advanced malignancies (cancer) or severe frailty.

Why is obesity such a major risk factor for OA?

BMI is 42.2 (obesity is a massive risk factor; every 1kg of body weight places ~4kg of pressure on each knee).

How can OA morning stiffness help distinguish it from RA?

His morning stiffness lasts approximately 30 minutes (this short duration is a classic hallmark of OA, differentiating it from the prolonged >1-hour stiffness seen in Rheumatoid Arthritis).

Why does ibuprofen relieve OA pain but worsen indigestion?

Ibuprofen relieves his pain by inhibiting the COX-2 driven prostaglandins causing the acute flare, but it is worsening his night-time indigestion (due to COX-1 inhibition in the stomach).

Explain the pathophysiology of jaundice in liver cancer.

The yellowing of the skin (jaundice) occurs because the liver tumour is obstructing bile ducts or destroying hepatocytes, leading to a toxic build-up of bilirubin in the blood.

Why is AFP useful in hepatocellular carcinoma?

A blood test for Alpha-fetoprotein (AFP) would be highly indicative of liver cancer (Hepatocellular carcinoma).

Define pain according to the IASP.

"An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of that damage."

Differentiate acute and chronic pain.

Acute pain is short-term and protective, usually due to an injury or surgery. Chronic pain persists beyond the normal healing time (typically >3-6 months) and often loses its protective physiological function, becoming a disease state in itself.

Define nociception.

Nociception is the physiological process of detecting tissue damage (it is not the same as "pain," which is the brain's perception of that signal).

Explain how nociceptors generate action potentials.

When triggered, ion channels (e.g., Acid-Sensing Ion Channels or ASIC) open, allowing an influx of sodium that depolarizes the cell and generates an action potential.

Compare Aδ fibres and C-fibres.

Aδ (A-delta) Fibres: Thinly myelinated and fast-conducting. They transmit sharp, pricking, and highly localized pain. C-Fibres: Unmyelinated and slow-conducting. They transmit dull, aching, throbbing, and poorly localized pain.

Describe the first-order neurone in the ascending pain pathway.

The nociceptor detects the stimulus. Its cell body sits in the Dorsal Root Ganglion (DRG) just outside the spinal cord. The signal travels along the central axon into the dorsal horn of the spinal cord.

Describe the second-order neurone in pain transmission.

Inside the dorsal horn, the first-order neurone releases excitatory neurotransmitters (primarily Glutamate binding to AMPA/NMDA receptors, and Substance P). The second-order neurone then decussates and ascends to the brain via the Lateral Spinothalamic Tract.

Describe the role of the thalamus in pain perception.

The signal arrives at the Thalamus (specifically the VPL and VPM nuclei), which acts as a relay station. The thalamus sends the signal to the Somatosensory Cortex and to the Limbic System / Prefrontal Cortex.

Explain descending pain modulation.

The Periaqueductal Gray (PAG) in the midbrain receives emotional and cognitive inputs. It signals the Nucleus Raphe Magnus (NRM) in the medulla and the Locus Coeruleus (LC) in the pons.

Which neurotransmitters mediate descending inhibition?

These structures send descending nerve fibres back down to the dorsal horn, releasing Serotonin and Noradrenaline. These neurotransmitters activate inhibitory interneurons that release GABA, hyperpolarising the second-order neurones and blocking the upward transmission of pain.

Explain the role of endogenous opioids.

The body produces natural painkillers (endorphins, enkephalins) that bind to Mu (µ) opioid receptors in the brain and spinal cord, powerfully suppressing pain transmission.

Explain Gate Control Theory.

Aβ fibres are thick, highly myelinated fibres that transmit harmless sensations like touch, rubbing, or vibration. When activated, they stimulate inhibitory interneurons in the dorsal horn, effectively "closing the gate" on the slower Aδ and C-fibre pain signals trying to reach the brain.

Describe nociceptive somatic pain.

Damage to skin, muscle, or bone. Transmitted densely by Aδ and C-fibres, making it sharp and highly localized.

Describe nociceptive visceral pain.

Damage to internal organs (stretching, ischemia). Transmitted by few nerve fibres, making it dull, cramping, and poorly localized. It frequently causes referred pain. where the pain is felt in a different area than where the injury occurs

Explain peripheral sensitization.

Damaged nerves alter their ion channels, lowering their activation threshold and causing spontaneous ectopic firing.