Para-Clinical Pathology Flashcards

24 sample cards from the Pathology deck

Sampled from the end of the deck, so these are different cards from the ones shown on the syllabus page.

1. What is the normal human karyotype, and how are numerical vs structural chromosomal abnormalities defined?

   Normal karyotype is 46,XX (female) or 46,XY (male) — 46 chromosomes total. Numerical abnormalities are gains/losses of whole chromosomes (aneuploidy, e.g., trisomy/monosomy, usually from nondisjunction; or polyploidy). Structural abnormalities involve breaks: deletions, translocations, inversions, isochromosomes, and ring chromosomes.

2. Give the karyotypes and key features of Down, Klinefelter, and Turner syndromes.

   Down syndrome: trisomy 21 (47,XX or XY,+21); intellectual disability, flat facies, congenital heart defects. Klinefelter: 47,XXY; tall male, hypogonadism, gynecomastia, infertility. Turner: 45,X (monosomy X); short female, webbed neck, ovarian dysgenesis (streak gonads), coarctation of the aorta.

3. What is Robertsonian translocation and its clinical importance in Down syndrome?

   A Robertsonian translocation is fusion of the long arms of two acrocentric chromosomes (e.g., 13, 14, 15, 21, 22) with loss of the short arms. In Down syndrome, translocation of extra chromosome 21 material (e.g., der(14;21)) means a phenotypically normal carrier parent has a high recurrence risk in offspring.

4. Define multifactorial (polygenic) inheritance and its characteristics.

   Multifactorial disorders result from the combined effects of MULTIPLE genes (each of small effect) plus environmental factors. Characteristics: familial clustering without a Mendelian pattern, risk increases with number of affected relatives and severity, and there is a threshold effect. Examples: hypertension, diabetes mellitus, cleft lip/palate, neural tube defects, coronary artery disease.

5. Explain trinucleotide (triplet) repeat mutations and give two examples.

   Trinucleotide repeat disorders arise from amplification of a repeating 3-nucleotide sequence, showing ANTICIPATION (worsening severity/earlier onset in successive generations). Examples: Fragile X syndrome ($\ce{CGG}$ repeats in FMR1), Huntington disease ($\ce{CAG}$ repeats in HTT), and myotonic dystrophy ($\ce{CTG}$).

6. What are the key features of mitochondrial (maternal) inheritance?

   Mitochondrial DNA is inherited exclusively from the mother (maternal inheritance); an affected mother transmits to ALL children, but only daughters pass it on. Features heteroplasmy (variable mutant mtDNA proportion) and affects high-energy tissues. Example: Leber hereditary optic neuropathy (LHON).

7. Explain genomic imprinting with the classic example of Prader-Willi vs Angelman syndrome.

   Genomic imprinting is parent-of-origin-specific silencing of a gene. Both map to chromosome 15q. Prader-Willi syndrome results from loss of the PATERNAL gene copy (hyperphagia, obesity, hypotonia). Angelman syndrome results from loss of the MATERNAL copy (ataxia, seizures, inappropriate laughter — 'happy puppet').

8. Distinguish oncogenes, tumor suppressor genes, and their mechanisms of activation/inactivation.

   Oncogenes are mutated/overexpressed proto-oncogenes that promote autonomous growth; a single (dominant) allele activation suffices (gain of function). Tumor suppressor genes normally inhibit proliferation; BOTH alleles must be inactivated (Knudson two-hit hypothesis, loss of function) — e.g., RB, TP53, APC.

9. State the six classic hallmarks of cancer (Hanahan and Weinberg).

   (1) Self-sufficiency in growth signals, (2) Insensitivity to growth-inhibitory (antigrowth) signals, (3) Evasion of apoptosis, (4) Limitless replicative potential (immortality, telomerase), (5) Sustained angiogenesis, and (6) Ability to invade and metastasize. (Later additions: reprogrammed metabolism and immune evasion.)

10. Differentiate benign and malignant neoplasms on differentiation, growth rate, invasion, and metastasis.

    Benign: well differentiated, slow growth, encapsulated/non-invasive, no metastasis (e.g., adenoma). Malignant: variable differentiation (may be anaplastic), rapid/erratic growth with many mitoses, locally invasive with irregular margins, and can metastasize (e.g., carcinoma).

11. Define anaplasia and list its cytologic features.

    Anaplasia means 'lack of differentiation' and is a hallmark of malignancy. Features: pleomorphism (variation in cell/nuclear size and shape), hyperchromatic nuclei with a high nuclear-to-cytoplasmic ratio (approaching $1:1$ vs the normal $1:4$–$1:6$), prominent nucleoli, abnormal/atypical mitoses, and loss of polarity.

12. Give the nomenclature rules: adenoma, carcinoma, sarcoma, -oma exceptions.

    Benign epithelial or mesenchymal tumors end in '-oma' (adenoma, lipoma). Malignant epithelial tumors = carcinomas; malignant mesenchymal tumors = sarcomas. Misleading '-oma' malignancies: lymphoma, melanoma, seminoma, mesothelioma, glioma. Teratoma arises from more than one germ layer; hamartoma and choristoma are non-neoplastic.

13. Compare the three main routes of metastatic spread and the typical tumors using each.

    (1) Lymphatic spread — typical of carcinomas (to regional lymph nodes). (2) Hematogenous spread — typical of sarcomas (and some carcinomas); liver and lungs are common sites via portal/caval drainage. (3) Seeding of body cavities — e.g., ovarian carcinoma spreading transcoelomically across the peritoneum.

14. Explain the multistep model of carcinogenesis and the role of driver vs passenger mutations.

    Carcinogenesis is a multistep accumulation of mutations: initiation (permanent DNA damage), promotion (clonal expansion), and progression (acquisition of additional malignant traits). Driver mutations confer selective growth advantage and drive cancer; passenger mutations are neutral bystanders that accumulate but do not contribute to the malignant phenotype.

15. Describe the RB gene and the cell cycle checkpoint it controls.

    RB is a tumor suppressor that governs the $G_1 \to S$ checkpoint. Hypophosphorylated (active) RB binds E2F, blocking transcription of S-phase genes. Growth signals activate cyclin D–CDK4/6 to phosphorylate RB, releasing E2F and allowing progression. Loss of RB (or of p16/INK4a) removes this brake, causing uncontrolled proliferation.

16. Why is TP53 called 'the guardian of the genome,' and what does it do after DNA damage?

    p53 senses DNA damage and either arrests the cell cycle at $G_1/S$ (via transcription of p21, a CDK inhibitor) to allow DNA repair, or triggers apoptosis (via BAX/PUMA) if damage is irreparable. It also induces senescence. TP53 is the most commonly mutated gene in human cancers; germline loss causes Li-Fraumeni syndrome.

17. Define oncogene addiction and give an example of a targeted therapy exploiting it.

    Oncogene addiction is the dependence of a tumor on the continued activity of a single driver oncogene for survival, making that oncogene a therapeutic target. Example: imatinib inhibits the BCR-ABL fusion tyrosine kinase (t(9;22), Philadelphia chromosome) in chronic myeloid leukemia; trastuzumab targets HER2 in breast cancer.

18. What is the Warburg effect in cancer metabolism?

    The Warburg effect is the tendency of cancer cells to rely on aerobic glycolysis — metabolizing glucose to lactate even in the presence of oxygen ($\ce{glucose -> 2\, lactate}$) — rather than oxidative phosphorylation. This provides rapid ATP and biosynthetic intermediates for proliferation and is the basis of FDG-PET tumor imaging.

19. List the major DNA repair systems and a cancer syndrome linked to each defect.

    Mismatch repair defect → hereditary nonpolyposis colorectal cancer (Lynch syndrome, microsatellite instability). Nucleotide excision repair defect → xeroderma pigmentosum (UV sensitivity, skin cancers). Homologous recombination defect → BRCA1/BRCA2 mutations (breast/ovarian cancer) and Fanconi anemia.

20. Define paraneoplastic syndrome and give two classic hormone examples.

    A paraneoplastic syndrome is a tumor-associated symptom complex not explained by local tumor spread or hormones normal to the tissue. Examples: small cell lung carcinoma producing ACTH (Cushing syndrome) or ADH (SIADH); squamous cell lung carcinoma producing PTHrP (hypercalcemia).

21. What are tumor grading and staging, and which better predicts prognosis?

    Grading assesses the degree of differentiation/anaplasia and mitotic activity (how the tumor LOOKS). Staging assesses the extent of spread using the TNM system — Tumor size/extent, regional lymph Nodes, distant Metastasis. Staging has greater prognostic value than grading.

22. Explain the adenoma-carcinoma sequence in colorectal cancer with key gene changes.

    Normal epithelium → (APC loss on 5q) → hyperproliferative epithelium/adenoma → (KRAS activation) → adenoma growth → (loss of tumor suppressors on 18q, e.g., SMAD4) → (TP53 loss on 17p) → carcinoma. Accumulation of these sequential mutations, not their order alone, drives malignant transformation.

23. Define telomeres and telomerase and their role in cancer immortality.

    Telomeres are repetitive $\ce{TTAGGG}$ sequences capping chromosome ends that shorten with each division, eventually triggering senescence. Telomerase, a reverse transcriptase, rebuilds telomeres. It is silent in most somatic cells but reactivated in ~90% of cancers, granting limitless replicative potential (immortality).

24. Name the major chemical, radiation, and microbial (viral) carcinogens with an associated cancer.

    Chemical: aflatoxin B1 (hepatocellular carcinoma, TP53 mutation), vinyl chloride (hepatic angiosarcoma), benzene (leukemia). Radiation: UV (skin cancers), ionizing radiation (leukemia, thyroid). Viral: HPV (cervical cancer, E6/E7 inactivate p53/RB), HBV/HCV (liver), EBV (Burkitt lymphoma, nasopharyngeal carcinoma), HTLV-1 (adult T-cell leukemia).

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