Master Pathology
for PMDC NLE Step 1

What the PMDC NLE Step 1 Tests in Pathology

The PMDC NLE Step 1 Pathology section tests your ability to diagnose and manage common and critical diseases based on histopathology, clinical presentation, and laboratory findings. You must know specific diagnostic criteria (e.g., WHO classification for tumours, TNM staging), first-line pharmacotherapy (e.g., tamoxifen for ER+ breast cancer), and key cut-off values (e.g., PSA >4 ng/mL, HbA1c ≥6.5%). Emphasis is on linking pathogenesis to clinical decisions—e.g., why Helicobacter pylori causes MALT lymphoma, or why KRAS mutation predicts poor response to anti-EGFR therapy in colorectal cancer. Questions often present a vignette with biopsy or lab results; you must select the correct diagnosis, next step in management, or prognostic marker. British conventions apply: use mg/dL for glucose, mmol/L for electrolytes, and staging per AJCC 8th edition.

High-Yield Concepts

• TNM Staging for Breast Cancer: T1: tumour ≤2 cm; T2: 2–5 cm; T3: >5 cm; T4: chest wall/skin involvement. N0: no nodal metastasis; N1: 1–3 axillary nodes; N2: 4–9 nodes; N3: ≥10 nodes or infraclavicular/supraclavicular nodes. M0: no distant metastasis; M1: distant spread. Use AJCC 8th edition; always check ER/PR/HER2 status for prognostic grouping.
• WHO Classification of CNS Tumours: Grade I: pilocytic astrocytoma (benign, curable by resection). Grade II: diffuse astrocytoma (infiltrative, IDH-mutant). Grade III: anaplastic astrocytoma (mitotic activity). Grade IV: glioblastoma (microvascular proliferation, necrosis, IDH-wildtype typically). IDH1 R132H mutation is diagnostic for lower-grade gliomas and confers better prognosis.
• Gleason Grading for Prostate Cancer: Score = primary grade + secondary grade (each 1–5). Grade 1: well-formed glands; Grade 5: no glands, sheets of cells. Clinically significant: Gleason ≥7 (4+3 worse than 3+4). PSA >4 ng/mL prompts biopsy; first-line treatment for localised disease: radical prostatectomy or radiotherapy with androgen deprivation therapy for high-risk.
• Dukes Staging for Colorectal Cancer: Dukes A: tumour confined to mucosa/submucosa (no nodal involvement). Dukes B: through muscularis propria, no nodes. Dukes C: regional lymph node metastasis. Dukes D: distant metastasis. Corresponding AJCC: Stage I (T1-2 N0 M0), Stage II (T3-4 N0 M0), Stage III (any T N1-2 M0), Stage IV (M1). Adjuvant chemotherapy (FOLFOX) indicated for Stage III and high-risk Stage II.
• KRAS and EGFR Mutations in Lung Adenocarcinoma: KRAS mutation (codon 12/13) predicts resistance to EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib). EGFR mutations (exon 19 deletion, L858R) confer sensitivity to TKIs. First-line: osimertinib for EGFR-mutant; immunotherapy (pembrolizumab) if PD-L1 ≥50% and no driver mutation. Testing mandatory before targeted therapy.
• HER2 Testing in Breast Cancer: IHC 0/1+: negative; IHC 3+: positive. IHC 2+: equivocal, requires FISH/CISH for HER2 gene amplification (ratio >2.0). Positive HER2: first-line trastuzumab + pertuzumab + chemotherapy. Trastuzumab emtansine (T-DM1) for residual disease after neoadjuvant therapy. Cardiotoxicity monitoring with echocardiogram every 3 months.
• Mismatch Repair Deficiency and Microsatellite Instability: Lynch syndrome: germline mutation in MLH1, MSH2, MSH6, PMS2. Tumours show loss of MMR protein expression by IHC (MLH1/PMS2 or MSH2/MSH6 absent). MSI-H by PCR (≥2 of 5 markers unstable). Associated with right-sided colon cancer, endometrial cancer. Checkpoint inhibitor (pembrolizumab) approved for MSI-H solid tumours regardless of site.
• Philadelphia Chromosome in CML: t(9;22)(q34;q11) leading to BCR-ABL1 fusion. Diagnostic by FISH or RT-PCR. Chronic phase: first-line imatinib 400 mg daily. Monitor BCR-ABL1 transcript levels; major molecular response (MMR) = ≤0.1% on international scale. Failure: switch to dasatinib or nilotinib. Blast crisis: treat as acute leukaemia (e.g., ALL-type therapy).

Common Traps in Pathology Questions

• Confusing Dukes B with Dukes C: Dukes B has no nodal involvement, Dukes C has positive nodes; always check for lymph node status in the vignette.
• Assuming KRAS mutation predicts response to EGFR inhibitors: it actually predicts resistance; only wild-type KRAS benefits from cetuximab/panitumumab in colorectal cancer.
• Mixing up Gleason grades with scores: grade is 1–5, score is sum of two grades; a score of 7 can be 3+4 (better prognosis) or 4+3 (worse prognosis).
• Thinking HER2 IHC 2+ is positive: it is equivocal and requires FISH confirmation; never treat based on IHC 2+ alone.
• Forgetting that MSI-H testing is indicated in all colorectal cancers under age 70 for Lynch syndrome screening, not just in older patients.
• Believing that all glioblastomas are IDH-mutant: most are IDH-wildtype; IDH mutation defines a distinct entity with better prognosis.

How to Revise Pathology for the PMDC NLE Step 1

Prioritise memorising TNM staging for breast, lung, and colorectal cancers, WHO grading for CNS tumours, and Gleason scoring for prostate. Focus on molecular markers (ER/PR/HER2, KRAS, EGFR, MSI, BCR-ABL) as they drive treatment decisions. Practice vignettes that present a biopsy report or lab result and ask for the next management step (e.g., 'What first-line therapy?' or 'What prognostic marker?'). Review AJCC 8th edition tables and WHO blue book summaries. Use flashcards for cut-off values (e.g., PSA >4 ng/mL, HbA1c ≥6.5%, BCR-ABL MMR ≤0.1%). Questions are clinically oriented—expect no pure histology recall; instead, link pathology to therapy. Allocate 30% of study time to tumour pathology, 20% to inflammatory/infectious pathology (e.g., granulomas in TB, H. pylori in gastritis), and 10% to genetic syndromes (Lynch, Li-Fraumeni, FAP).

Practise it: MedLumen has 50 Pathology questions for the PMDC NLE Step 1, each with a full explanation and references.