Pathology
MBBS Pathology — high-yield long questions and short notes from Robbins & Cotran and Harsh Mohan, covering general pathology (cell injury, inflammation, haemodynamics, immunopathology, neoplasia), haematology, and systemic pathology of the cardiovascular, respiratory, GI, hepatobiliary, renal, endocrine and other systems, written to the marks with definitions, mechanisms, morphology, classification, clinical correlation and pearls.
12chapters144questions99High-Yield
Definition
A neoplasm is an abnormal mass of tissue with uncoordinated, excessive growth that persists after the stimulus is withdrawn; it may be benign or malignant.
Benign Tumour
- Slow growth, expansile; usually encapsulated
- Well differentiated, resembles tissue of origin
- Few mitoses, no atypia; no invasion, no metastasis
- Rarely recurs after complete excision
- Named with suffix -oma (lipoma, adenoma)
Malignant Tumour
- Rapid growth, infiltrative; non-encapsulated
- Poorly differentiated / anaplastic — pleomorphism, hyperchromatic nuclei, high nucleo-cytoplasmic ratio, abnormal mitoses
- Invasion and metastasis — the definitive feature
- Necrosis, haemorrhage, ulceration common; recurs after excision
- Carcinoma (epithelial) or sarcoma (mesenchymal)
Breaching the basement membrane is the critical step to malignancy. Feature Benign Malignant Growth Slow Rapid Capsule Present Absent Differentiation Good Poor/anaplastic Metastasis Never Characteristic Applied
- Benign tumours may still kill by site (meningioma) or hormone secretion (insulinoma)
- Metastasis is the single most reliable sign of malignancy
🔑KEY POINTS TO REMEMBER- Benign: slow, encapsulated, well differentiated, no metastasis.
- Malignant: infiltrative, anaplastic, abnormal mitoses, metastasises.
- Metastasis is the most reliable feature of malignancy.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Carcinogenesis is the multistep process by which normal cells acquire genetic changes that transform them into malignant cells.
Genetic Basis (four gene classes)
- Oncogenes — gain of function: RAS, MYC, HER2, ABL
- Tumour-suppressor genes — loss of function: p53 (‘guardian of the genome’), Rb, APC, BRCA
- Apoptosis-regulating genes — BCL-2
- DNA repair genes — mismatch repair (HNPCC), xeroderma pigmentosum
Carcinogenic Agents
- Chemical — initiation then promotion; polycyclic hydrocarbons (smoking), aflatoxin (liver), aniline dyes (bladder), asbestos
- Radiation — ultraviolet (skin), ionising (leukaemia, thyroid)
- Viral — HPV (cervix), EBV (lymphoma), HBV/HCV (liver), HTLV-1, HHV-8
- H. pylori — gastric carcinoma and MALT lymphoma
Cancer needs an accumulation of mutations, not a single hit. Gene Type Cancer RAS Oncogene Colon, lung p53 Suppressor Many Rb Suppressor Retinoblastoma Applied
- Knudson two-hit hypothesis explains hereditary retinoblastoma
- p53 is the commonest mutated gene in human cancer
🔑KEY POINTS TO REMEMBER- Carcinogenesis is multistep: oncogenes, suppressors, apoptosis and repair genes.
- Agents: chemical (initiation-promotion), radiation, viruses, H. pylori.
- p53 is the most frequently mutated gene; two-hit hypothesis for suppressors.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Metastasis is the spread of tumour to sites physically discontinuous with the primary, and is the hallmark of malignancy.
Metastatic Cascade
- Loosening of tumour cells — loss of E-cadherin
- Attachment to basement membrane (laminin, fibronectin receptors)
- Degradation by matrix metalloproteinases (collagenase)
- Migration and intravasation into vessels
- Survival in circulation (platelet aggregates), arrest, extravasation
- Angiogenesis (VEGF) and growth at the new site
Routes & Organ Tropism
- Lymphatic — carcinomas; haematogenous — sarcomas
- Transcoelomic (peritoneal, pleural), perineural, direct implantation
- ‘Seed and soil’ hypothesis explains organ preference
- Common sites: liver, lung, bone, brain
Each step must succeed for a metastatic deposit to establish. Tumour Preferred spread Carcinoma Lymphatic Sarcoma Blood Ovarian carcinoma Transcoelomic Applied
- Krukenberg tumour — bilateral ovarian metastases from stomach
- Virchow node — left supraclavicular node from gastric carcinoma
🔑KEY POINTS TO REMEMBER- Metastatic cascade: detachment (E-cadherin loss), MMP degradation, intravasation, extravasation.
- Carcinomas spread lymphatically; sarcomas haematogenously.
- Seed and soil hypothesis explains organ tropism.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Grading assesses the degree of tumour differentiation (microscopic), while staging assesses the anatomical extent of spread.
Grading
- Based on degree of differentiation, pleomorphism and mitotic rate
- Grade I — well differentiated; Grade II — moderately; Grade III — poorly; Grade IV — anaplastic
- Determined by the pathologist on histology
- Broders’ grading; Gleason score for prostate; Bloom-Richardson for breast
Staging
- TNM system: T = tumour size/extent, N = nodal involvement, M = distant metastasis
- Stages I–IV; also AJCC and Dukes (colorectal) systems
- Assessed clinically, radiologically and surgically
- Staging is more important than grading for prognosis and treatment
Grade describes aggressiveness; stage describes extent. Feature Grading Staging Basis Differentiation Spread Method Microscopy Clinical + imaging Prognosis Less useful More useful Applied
- TNM guides the choice of surgery, chemotherapy or radiotherapy
- High grade with low stage may still be curable
🔑KEY POINTS TO REMEMBER- Grading = degree of differentiation (microscopic, Grades I–IV).
- Staging = anatomical extent (TNM system).
- Staging has greater prognostic value than grading.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Tumour nomenclature is based on the tissue of origin and on whether the tumour is benign or malignant.
General Rules
- Benign — tissue name + ‘-oma’: lipoma, fibroma, adenoma, chondroma
- Malignant epithelial → carcinoma: adenocarcinoma, squamous cell carcinoma
- Malignant mesenchymal → sarcoma: osteosarcoma, liposarcoma, leiomyosarcoma
- Mixed tumours — pleomorphic adenoma of salivary gland
- Teratoma — all three germ layers (totipotent cells)
Exceptions to the Rule
- Malignant despite ‘-oma’: melanoma, lymphoma, seminoma, mesothelioma, glioma, hepatoma
- Hamartoma — disorganised mass of tissue native to the site (not a true tumour)
- Choristoma — normal tissue in an ectopic site
- Blastomas — embryonal tumours of children (nephroblastoma, neuroblastoma)
Tissue of origin plus behaviour generates the tumour name. Tissue Benign Malignant Fat Lipoma Liposarcoma Gland Adenoma Adenocarcinoma Bone Osteoma Osteosarcoma Applied
- Remember the ‘-oma’ exceptions — commonly asked
- Hamartoma and choristoma are developmental, not neoplastic
🔑KEY POINTS TO REMEMBER- Benign tumours end in ‘-oma’; malignant epithelial = carcinoma, mesenchymal = sarcoma.
- Exceptions: melanoma, lymphoma, seminoma, mesothelioma are malignant.
- Hamartoma (native tissue) and choristoma (ectopic tissue) are not true tumours.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Benign and malignant tumours are distinguished by differentiation, growth pattern, local invasion and capacity to metastasise.
Distinguishing Features
- Differentiation — benign well differentiated; malignant poorly differentiated or anaplastic
- Rate of growth — slow vs rapid, with many abnormal mitoses
- Local invasion — benign expansile and encapsulated; malignant infiltrative
- Metastasis — absent in benign; diagnostic of malignancy
Features of Anaplasia
- Pleomorphism (variation in size and shape)
- Hyperchromatic nuclei; high nucleo-cytoplasmic ratio
- Prominent nucleoli; atypical mitotic figures
- Loss of polarity, tumour giant cells, necrosis
Invasion and metastasis define malignant behaviour. Feature Benign Malignant Capsule Present Absent Mitoses Few, normal Many, atypical Necrosis Rare Common Metastasis Absent Present Applied
- Benign tumours can be lethal by location or hormone production
- Metastasis is the most reliable indicator of malignancy
🔑KEY POINTS TO REMEMBER- Four criteria: differentiation, growth rate, local invasion, metastasis.
- Anaplasia: pleomorphism, hyperchromasia, atypical mitoses.
- Metastasis is the definitive proof of malignancy.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Routes of metastasis are the pathways by which malignant cells spread from the primary tumour to distant sites.
Main Routes
- Lymphatic — typical of carcinomas; to regional lymph nodes first
- Haematogenous (blood) — typical of sarcomas; veins invaded more often than arteries; to liver and lung
- Transcoelomic — across body cavities: ovarian and gastric carcinoma → peritoneum
- Perineural — adenoid cystic carcinoma, prostate, pancreas
- Direct implantation — surgical or needle-track seeding
Characteristic Examples
- Krukenberg tumour — bilateral ovarian deposits from gastric signet-ring carcinoma
- Virchow node — left supraclavicular node from stomach
- Batson venous plexus — prostate carcinoma to vertebrae
- Bone metastases: breast, prostate, lung, thyroid, kidney
The route taken shapes where secondaries appear. Route Tumour Lymphatic Carcinoma Blood Sarcoma Transcoelomic Ovarian Applied
- Sentinel node biopsy identifies the first draining node
- Metastatic pattern guides staging investigations
🔑KEY POINTS TO REMEMBER- Routes: lymphatic, haematogenous, transcoelomic, perineural, implantation.
- Carcinomas favour lymphatics; sarcomas favour blood.
- Krukenberg tumour and Virchow node are classic examples.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Carcinoma is a malignant tumour of epithelial origin, whereas sarcoma arises from mesenchymal (connective) tissue.
Carcinoma
- Origin: epithelium (skin, gland, mucosa)
- Commoner; usually in older adults
- Spreads mainly by lymphatics first
- Gross: firm, grey-white, infiltrative; microscopically forms nests or glands
- Cytokeratin positive on immunohistochemistry
Sarcoma
- Origin: connective tissue — bone, muscle, fat, cartilage, vessels
- Rarer; often in younger patients
- Spreads mainly by blood to lungs
- Gross: soft, fleshy, fish-flesh appearance
- Vimentin positive
Tissue of origin determines both appearance and route of spread. Feature Carcinoma Sarcoma Origin Epithelial Mesenchymal Spread Lymphatic Haematogenous Marker Cytokeratin Vimentin Applied
- Immunohistochemistry resolves poorly differentiated tumours
- Sarcomas need early chest imaging for lung metastases
🔑KEY POINTS TO REMEMBER- Carcinoma is epithelial and spreads via lymphatics (cytokeratin positive).
- Sarcoma is mesenchymal and spreads via blood to lungs (vimentin positive).
- Carcinomas are far commoner and occur in older patients.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Tumour markers are substances produced by tumours or by the host in response to tumour, detectable in blood or tissue.
Important Markers
- AFP — hepatocellular carcinoma, non-seminomatous germ cell tumours
- β-hCG — choriocarcinoma, hydatidiform mole, germ cell tumours
- CEA — colorectal, pancreatic, gastric carcinoma
- PSA — prostate carcinoma
- CA-125 — ovarian; CA 19-9 — pancreatic; CA 15-3 — breast
- Calcitonin — medullary thyroid carcinoma; catecholamines/VMA — phaeochromocytoma, neuroblastoma
Uses & Limitations
- Best for monitoring treatment response and detecting recurrence
- Not reliable for screening (except PSA in selected settings)
- Raised in benign conditions too — low specificity
- Normal levels do not exclude cancer
Serial values matter far more than a single reading. Marker Tumour AFP Hepatocellular carcinoma β-hCG Choriocarcinoma PSA Prostate CA-125 Ovarian Applied
- AFP is also raised in pregnancy and cirrhosis
- Diagnosis still requires histopathology
🔑KEY POINTS TO REMEMBER- Key markers: AFP (liver), β-hCG (choriocarcinoma), CEA (colon), PSA (prostate), CA-125 (ovary).
- Chiefly used for monitoring therapy and detecting recurrence.
- Poor specificity — not diagnostic on their own.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Grading describes how abnormal tumour cells look, while staging describes how far the tumour has spread.
Grading
- Microscopic assessment by the pathologist
- Based on differentiation, pleomorphism and mitotic count
- Grade I (well differentiated) to Grade IV (anaplastic)
- Specific systems: Gleason (prostate), Bloom-Richardson (breast), Fuhrman (kidney)
Staging
- Anatomical extent — assessed clinically, radiologically, surgically
- TNM: T (size/local extent), N (nodes), M (metastasis)
- Stage I–IV; Dukes staging for colorectal carcinoma
- Greater prognostic value and determines treatment
Grade is what the cells look like; stage is where they have gone. Feature Grading Staging Assessed by Microscopy Clinical/imaging Basis Differentiation T, N, M Prognostic value Lower Higher Applied
- Staging decides between curative surgery and palliative therapy
- Both are recorded together in the pathology report
🔑KEY POINTS TO REMEMBER- Grading is microscopic (differentiation, mitoses), Grades I–IV.
- Staging is anatomical extent, using the TNM system.
- Stage is more important than grade for prognosis and management.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Paraneoplastic syndromes are symptom complexes in cancer patients that cannot be explained by the tumour mass or its metastases.
Endocrine Syndromes
- SIADH — small cell carcinoma of lung → hyponatraemia
- Cushing syndrome — ectopic ACTH; small cell lung carcinoma
- Hypercalcaemia — PTH-related peptide; squamous cell carcinoma of lung, renal cell carcinoma
- Hypoglycaemia — insulin-like factors (hepatocellular carcinoma, sarcoma)
- Polycythaemia — erythropoietin (renal cell carcinoma)
Other Syndromes
- Neurological — Lambert-Eaton myasthenic syndrome, cerebellar degeneration
- Dermatological — acanthosis nigricans (gastric carcinoma), dermatomyositis
- Haematological — migratory thrombophlebitis (Trousseau sign, pancreatic carcinoma), DIC
- Osseous — hypertrophic osteoarthropathy and clubbing (lung carcinoma)
- Nephrotic syndrome, fever, cachexia
These syndromes can be the first clue to an occult cancer. Syndrome Tumour SIADH Small cell lung Hypercalcaemia Squamous cell lung Acanthosis nigricans Gastric Applied
- May be the earliest manifestation of an occult tumour
- Symptoms regress when the tumour is treated
🔑KEY POINTS TO REMEMBER- Paraneoplastic syndromes are not explained by tumour mass or metastasis.
- SIADH and ectopic ACTH from small cell lung cancer; hypercalcaemia from squamous cell.
- May be the earliest sign of an occult malignancy.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.Definition
Oncogenes promote cell proliferation when activated, while tumour-suppressor genes restrain growth and cause cancer when lost.
Oncogenes
- Derived from normal proto-oncogenes by mutation, amplification or translocation
- Dominant — a single mutated allele suffices (gain of function)
- RAS — point mutation; colon, lung, pancreas
- MYC — translocation t(8;14) in Burkitt lymphoma
- BCR-ABL — t(9;22) Philadelphia chromosome, CML
- HER2/neu — amplification in breast carcinoma
Tumour-Suppressor Genes
- Recessive — both alleles must be lost (Knudson two-hit hypothesis)
- p53 — ‘guardian of the genome’; arrests cycle, induces apoptosis; commonest mutation in cancer; Li-Fraumeni syndrome
- Rb — retinoblastoma, osteosarcoma
- APC — familial adenomatous polyposis; BRCA1/2 — breast and ovarian cancer
Accelerator stuck on, or brakes failed — both drive proliferation. Gene Type Tumour BCR-ABL Oncogene CML MYC Oncogene Burkitt p53 Suppressor Many Applied
- Imatinib targets BCR-ABL; trastuzumab targets HER2
- BRCA testing guides screening and risk-reducing surgery
🔑KEY POINTS TO REMEMBER- Oncogenes are dominant gain-of-function genes (RAS, MYC, BCR-ABL, HER2).
- Tumour suppressors are recessive — both alleles lost (two-hit hypothesis).
- p53 is the most commonly mutated gene in human cancer.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); Robbins Basic Pathology.