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ATAL BIHARI VAJPAYEE MEDICAL UNIVERSITY - M.D. PATHOLOGY (JAN 2025)

Recent Advances in Pathology - Complete Answers

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Q.1 - Role of Molecular Genetics and Genomics in Urothelial Bladder Cancer (15 Marks)

Introduction

Molecular Subtypes (Genomic Classification)

• Luminal-papillary - FGFR3/FOXA1 mutations; most favorable prognosis
• Luminal-infiltrated - EMT markers, immune evasion genes
• Luminal - PPARG pathway activation
• Basal-squamous - TP53, RB1 alterations; resembles basal breast cancer; aggressive
• Neuronal - most aggressive; neural differentiation markers

Key Genetic Alterations

FGFR3 and Targeted Therapy

• FGFR3 mutations (S249C most common) activate downstream RAS-MAPK and PI3K-AKT
• FGFR3 fusions (e.g., FGFR3-TACC3) also occur
• Erdafitinib - first FDA-approved FGFR inhibitor for metastatic UC with FGFR3/2 alterations (2019)
• Companion diagnostic: therascreen FGFR RGQ RT-PCR kit

DNA Damage Response (DDR) Genes

• ERCC2, ERCC5, ATM, BRCA1/2 mutations predict response to cisplatin-based chemotherapy
• ERCC2-mutant tumors show 5x improved response to neoadjuvant cisplatin

Genomic Instability and Immunotherapy Response

• High tumor mutational burden (TMB-High) in muscle-invasive UC (>10 mut/Mb) predicts immune checkpoint inhibitor (ICI) response
• Microsatellite instability (MSI-H) - pembrolizumab approved for all MSI-H tumors
• APOBEC mutagenesis (TC>TT/TC>TG signature) is the dominant mutational signature

Non-coding RNA and Epigenomics

• lncRNAs (e.g., MALAT1, H19) - promote progression
• miR-200 family downregulation - promotes EMT
• DNA methylation of CDH1, APC - early silencing events

Liquid Biopsy Applications

• TERT promoter mutation detection in urine - highly sensitive (>80%) for low-grade NMIBC surveillance
• Urine ctDNA panels outperform urine cytology (sensitivity 90% vs 20% for low-grade UC)
• CancerSEEK and CLOVIS multi-cancer panels include bladder

Clinicopathological Correlations

• NMIBC (Ta/T1): FGFR3 mutations, TERT promoter; low-grade, papillary
• MIBC (T2+): TP53, RB1, CDKN2A deletions; high-grade, aggressive
• Bacillus Calmette-Guerin (BCG) non-responders: PTPN11, KRAS mutations

Future Directions

• Molecular subtyping guiding neoadjuvant chemotherapy selection
• CDK4/6 inhibitors for RB1-intact luminal tumors
• ErbB family (HER2) amplification - 14% of MIBC - trastuzumab deruxtecan trials ongoing

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Q.2 - Liquid Biopsy in Metastatic Lung Adenocarcinoma (15 Marks)

a) What is liquid biopsy, and how does it aid in diagnosis and management of lung cancer? (4 marks)

• Initial diagnosis: Detect driver mutations (EGFR, ALK, ROS1, KRAS) when tissue is unavailable or insufficient
• Treatment selection: Identify targetable mutations for TKI therapy
• Real-time monitoring: Track treatment response (ctDNA levels fall with effective therapy)
• Resistance detection: Identify resistance mutations (e.g., EGFR T790M) before radiologic progression
• Minimal residual disease (MRD): Detect molecular relapse 3-12 months before clinical/radiologic recurrence

b) Role of ctDNA in identifying EGFR mutations (5 marks)

• Tumor cells release fragmented DNA (~160 bp) into the circulation via apoptosis and necrosis
• ctDNA represents 0.01-10% of total cell-free DNA (cfDNA); higher in advanced/metastatic disease
• ctDNA half-life is ~1-2 hours, making it an ideal real-time biomarker

• Sensitivity for T790M detection: ~70% vs tissue (gold standard ~95%)
• Clinical implication: A negative liquid biopsy does NOT exclude mutation - tissue biopsy is still required if ctDNA is negative

• ctDNA levels correlate with tumor burden
• Rising ctDNA on treatment = emerging resistance (clonal evolution)
• Serial ctDNA can track subclonal emergence of resistance (e.g., MET amplification, KRAS mutation, histologic transformation to SCLC)

c) Advantages and Limitations of Liquid Biopsy (3 marks)

• Non-invasive - only blood draw required
• Can be repeated serially (real-time monitoring)
• Captures intra-tumoral and inter-metastatic heterogeneity better than single-site biopsy
• Detects multiple resistance mechanisms simultaneously
• Useful when tissue biopsy is not feasible (poor performance status, inaccessible lesion, coagulopathy)
• Earlier detection of recurrence than imaging

• Lower sensitivity than tissue biopsy, especially for early-stage/low burden disease
• Cannot provide histologic information (e.g., SCLC transformation)
• False negatives in low-shedding tumors
• Lack of standardization across platforms
• High cost and limited availability in resource-limited settings
• Cannot assess tumor microenvironment or PD-L1 expression

d) Recent Advancements in Liquid Biopsy Technology (3 marks)

• Digital droplet PCR (ddPCR): Ultra-sensitive detection of known mutations (sensitivity 0.01%), better for low ctDNA fractions
• Next-Generation Sequencing (NGS) cfDNA panels: e.g., FoundationOne Liquid CDx - comprehensive 300+ gene panel; FDA-approved companion diagnostic
• Whole-genome sequencing of cfDNA (WGS-cfDNA): Copy number variation analysis, tumor fraction estimation
• Methylation-based cfDNA: CancerSEEK, Galleri (Grail) - tissue-of-origin identification
• Fragmentomics: ctDNA fragment size patterns predict tumor origin and type
• Exosome analysis: Tumor-derived exosomes carry proteins, RNA; more stable than ctDNA
• Epitranscriptomics: m6A modifications on circulating RNA as novel biomarkers
• Multi-analyte liquid biopsy: Combining ctDNA + protein biomarkers (CEA, CRP) improves sensitivity

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Q.3 - Role of PD-L1 Testing in Predicting Response to Immune Checkpoint Inhibitors (7 marks)

Background

Why PD-L1 Testing Matters

• Predictive biomarker (not just prognostic) for response to anti-PD-1/PD-L1 therapies
• Determines eligibility and treatment selection in multiple solid tumors
• Guides first-line vs. second-line use of immunotherapy

Scoring Systems

Approved Cutoffs and Drugs

Assay Platforms (The "4 Assays for 4 Drugs" Problem)

• 22C3 (Dako): Pembrolizumab - NSCLC TPS, gastric CPS
• 28-8 (Dako): Nivolumab - NSCLC, melanoma
• SP142 (Ventana): Atezolizumab - TNBC IC, urothelial IC
• SP263 (Ventana): Durvalumab - NSCLC

Limitations of PD-L1 as a Biomarker

• Spatial and temporal heterogeneity (PD-L1 expression varies within tumor and over time)
• Anti-PD-1/PD-L1 therapy works even in some PD-L1 negative tumors (e.g., MSI-H tumors)
• PD-L1 negative tumors can respond; PD-L1 high tumors can fail
• Pre-analytical factors (fixation time, ischemia) affect staining
• No universal cutoff across tumor types

Complementary/Alternative Biomarkers

• TMB-H (>10 mut/Mb): FDA-approved for pembrolizumab (tumor-agnostic) regardless of PD-L1
• MSI-H/dMMR: Strongest predictor - FDA-approved for pembrolizumab across all solid tumors
• Tumor-infiltrating lymphocytes (TILs): High TIL counts correlate with immunotherapy response in breast cancer
• LAG3, TIM3, TIGIT: Emerging checkpoint molecules for combination therapies

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Q.4 - Molecular Diagnostic Techniques in Hematological Malignancies (7 marks)

Overview

Key Molecular Techniques

• Detects gross chromosomal abnormalities (translocations, deletions, inversions)
• Remains gold standard for complex karyotype in AML and MDS
• Resolution: ~5-10 Mb

• Detects specific chromosomal rearrangements using fluorescent probes
• Key applications:
  • t(9;22) BCR-ABL1 - CML/Ph+ ALL
  • t(15;17) PML-RARA - APL
  • del(13q), del(17p), +12 - CLL risk stratification
  • t(11;14) IGH-CCND1 - Mantle cell lymphoma
  • MYC, BCL2, BCL6 rearrangements - "Double-hit" DLBCL

• Detects specific fusion transcripts and mutations
• BCR-ABL1 (p210/p190) quantification for CML MRD monitoring
• PML-RARA detection and MRD in APL
• MRD negativity <0.1% (IS) = major molecular response in CML

• Multigene panels (30-400 genes): FLT3, NPM1, DNMT3A, IDH1/2, TET2, RUNX1, ASXL1, TP53, SF3B1
• AML panel: FLT3-ITD and TKD, NPM1, IDH1/2 - determine prognosis and therapy (midostaurin for FLT3+; enasidenib/ivosidenib for IDH2/IDH1+)
• MDS panel: SF3B1 (ring sideroblasts), DNMT3A, TET2, ASXL1
• CLL panel: TP53, NOTCH1, SF3B1, BIRC3 - detect del17p/TP53 (ibrutinib preferred over chemotherapy)

• Research and specialized centers
• Identifies novel driver mutations, complex rearrangements, chromothripsis

• Fusion transcript discovery (e.g., NUP98 fusions in pediatric AML)
• Gene expression profiling
• Classifies B-ALL by transcriptional profile (Ph-like ALL)

• MRD monitoring with sensitivity 10^-5 to 10^-6
• BCR-ABL1, NPM1 MRD
• Detection of rare mutations

• DNA methylation profiling classifies CNS lymphomas and pediatric leukemias
• MethylationEPIC array (850K CpG sites)

• Immunophenotyping for leukemia/lymphoma subtyping
• MRD by MFC (multiparameter flow cytometry) - 10^-4 to 10^-5 sensitivity
• EuroFlow standardized panels for B-ALL, T-ALL, CLL, MGUS, myeloma

• Detects copy number variants and loss of heterozygosity
• Uniparental disomy (UPD) - important in MDS (UPD11q in AML)

Clinical Applications Summary

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Q.5 - Grey Zone Lymphoma (7 marks)

Definition

• Primary Mediastinal Large B-cell Lymphoma (PMBCL), AND
• Classic Hodgkin Lymphoma, Nodular Sclerosis type (CHL-NS)

Epidemiology

• Rare - accounts for <1% of all lymphomas
• Young adults (20-40 years); male predominance
• Typically presents with bulky anterior mediastinal mass
• Rapid progression; often presents with superior vena cava syndrome

Morphology and Immunophenotype

Pathogenesis and Molecular Features

• Both PMBCL and CHL-NS arise from germinal center B-cells of the thymic medulla
• Shared molecular features with both entities:
  • JAK2 amplification (9p24.1) - present in PMBCL and CHL
  • PD-L1 overexpression (9p24.1 amplification) - provides therapeutic target
  • NFkB pathway activation (TNFAIP3/A20 mutations)
  • CIITA translocations (affecting MHC class II expression)
  • Somatic hypermutation of IGV genes
• GZL represents a biological continuum - not simply one or the other

Diagnosis

• Requires integrated clinicopathological approach
• Core needle biopsy is often insufficient - excision biopsy preferred
• Flow cytometry plus IHC panel essential
• Molecular studies (FISH for MYC, BCL2, BCL6) to exclude double-hit lymphoma

Treatment and Prognosis

• Prognosis is generally worse than both PMBCL and CHL individually
• Standard treatment: dose-adjusted DA-EPOCH-R or R-CHOP (response rates lower than PMBCL)
• BV-DA-EPOCH (brentuximab vedotin - targets CD30) shows promise
• PD-1 inhibitors (nivolumab, pembrolizumab) - rationale from PD-L1 overexpression
• Consolidative radiotherapy often added for mediastinal disease
• 5-year OS: ~50-60% (worse than PMBCL at ~80%)

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Q.6 - STIC (Serous Tubal Intraepithelial Carcinoma) and Its Implications (7 marks)

Definition

• High-grade serous carcinoma of the ovary (HGSC)
• Primary peritoneal serous carcinoma
• High-grade serous carcinoma of the fallopian tube

Historical Background

• Traditionally, HGSC was thought to arise from the ovarian surface epithelium or cortical inclusion cysts
• The paradigm shifted when prophylactic salpingo-oophorectomy specimens from BRCA1/2 mutation carriers consistently showed STICs in the fimbriated end
• This led to the "fallopian tube origin hypothesis" for HGSC - one of the most significant paradigm shifts in gynecological oncology in the last two decades

Morphology of STIC

• Replacement of normal flat secretory cells by enlarged, atypical cells with:
  • Loss of normal cell polarity
  • Nuclear stratification
  • High nuclear-to-cytoplasmic ratio
  • Prominent nucleoli
  • Mitotic figures (including abnormal mitoses)
• Architecture: no invasion through basement membrane (intraepithelial)
• Location: fimbriated end (infundibulum) is the most common site
• SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriated end) - mandatory protocol for all salpingo-oophorectomy specimens to detect STIC

Molecular Features

• TP53 mutations - present in >90% of STICs (loss-of-function or gain-of-function hotspot mutations: R175H, R248W, R273H)
• TP53 signature precedes STIC - normal-appearing but TP53-mutant secretory cell clusters (p53 signatures) represent the earliest detectable change
• BRCA1/2 germline mutations - found in 30-50% of STIC-associated HGSCs
• Shared TP53 mutations between STIC and co-existing HGSC confirm clonal relationship
• Other alterations: CCNE1 amplification, PTEN loss, RB1 loss (occur later in progression)

Clinical Implications

• BRCA1/2 mutation carriers: risk-reducing bilateral salpingo-oophorectomy (RRBSO) remains the most effective prevention
• New debate: risk-reducing salpingectomy alone (RRS) at completion of childbearing, with delayed oophorectomy - reduces HGSC risk while preserving ovarian hormonal function
• Population-level opportunistic salpingectomy at time of other pelvic surgeries is now recommended by many gynecologic oncology societies

• SEE-FIM protocol mandatory in all resected fallopian tubes
• IHC panel: p53 (aberrant pattern - diffuse strong or complete loss), Ki-67 (elevated), PAX8 (secretory cell marker), EGFR

• STIC found without associated invasive carcinoma requires:
  • Complete staging workup
  • Enhanced surveillance (CA-125, imaging)
  • Genetic counseling and BRCA testing
  • Peritoneal washings assessment
  • Discussion of residual ovarian/peritoneal risk

• Scenario 1: STIC implants on ovary during ovulation - explains "ovarian" HGSC with fallopian tube origin
• Scenario 2: STIC sheds cells that implant peritoneally - explains primary peritoneal carcinoma
• Scenario 3: STIC directly invades - true fallopian tube carcinoma

• BRCA1/2 mutation confirmed HGSC: eligible for PARP inhibitor maintenance therapy (olaparib, niraparib, rucaparib)
• BRCAness phenotype (HRD score high even without BRCA mutation) also benefits from PARP inhibitors

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Q.7 - Chediak-Higashi Syndrome (7 marks)

Definition

Genetics and Pathogenesis

• Gene: LYST (Lysosomal Trafficking Regulator) gene, chromosome 1q42.1-q42.2
• LYST protein regulates vesicle fusion and fission, lysosome-related organelle biogenesis
• Mutations: Frameshift/nonsense mutations - severe childhood phenotype (classic); Missense mutations - milder adult phenotype (10-15% of cases)
• Pathomechanism: Dysregulated fission/fusion of lysosome-related organelles leads to:
  • Abnormally giant melanosomes (decreased melanin distribution) - silvery hair, hypopigmentation
  • Giant leukocyte cytolytic granules - cytotoxic T-cells and NK cells cannot discharge perforin/granzymes - immunodeficiency
  • Giant platelet dense granules - reduced ADP/serotonin release - mild bleeding diathesis
  • Defective autophagy - neurodegeneration

Clinical Features

• Partial oculocutaneous albinism: silvery-metallic hair sheen, diffuse skin hypopigmentation with areas of bronze/slate-gray hyperpigmentation in sun-exposed areas; photophobia, nystagmus, strabismus
• Recurrent pyogenic infections: primarily Staphylococcus aureus, Streptococcus pyogenes - skin and respiratory tract
• Mild bleeding diathesis: prolonged bleeding time, reduced platelet aggregation
• Peripheral neuropathy: in adolescence/adulthood

• Occurs in ~85% of patients (most commonly in childhood)
• Triggered by EBV or other viral infections
• Features: fever, hepatosplenomegaly, lymphadenopathy, pancytopenia (from bone marrow infiltration)
• Uncontrolled lymphohistiocytic proliferation and hemophagocytosis
• Fatal without treatment
• Pathologically: diffuse infiltration of multiple organs (liver, spleen, bone marrow, lymph nodes) by activated lymphocytes and macrophages

Diagnosis

• Blood smear: Giant azurophilic granules in neutrophils, eosinophils, monocytes, lymphocytes - PATHOGNOMONIC
• Bone marrow biopsy: Giant granules in myeloid precursors
• NK cell cytotoxicity assay: Markedly reduced
• Genetic confirmation: LYST gene sequencing
• Electron microscopy: Giant melanosomes, abnormal lysosomal structures
• Hair microscopy: Giant pigment clumps (vs. uniform small granules in normal hair)

Differential Diagnosis

• Griscelli syndrome types 1 and 2: Silvery hair but no giant granules; MYO5A (type 1) or RAB27A (type 2) mutations
• Hermansky-Pudlak syndrome: Oculocutaneous albinism + bleeding (platelet dense granule deficiency) - no immune deficiency; BLOC complex gene mutations
• Elejalde syndrome: Silvery hair, CNS disease, no immune deficiency

Treatment

• Definitive: Allogeneic hematopoietic stem cell transplantation (HSCT) - corrects hematopoietic defects; does NOT reverse neurological deterioration
• Accelerated phase: Dexamethasone + etoposide + cyclosporine (HLH-2004 protocol), followed by HSCT
• Infections: Aggressive prophylactic and therapeutic antibiotics
• Prognosis without HSCT: Death in first decade from accelerated phase or infections
• With HSCT: Improved survival but progressive neurological disease remains a challenge

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Q.8 - Recently Described Entities in Thyroid (7 marks)

Introduction

1. NIFTP - Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features

• Previously called: Encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) - non-invasive type
• Reclassified in 2016 (Nikiforov et al.) based on its indolent biology
• Features:
  • Complete fibrous capsule, no invasion (capsular or vascular)
  • Follicular architecture (no papillary structures, no psammoma bodies)
  • Nuclear features of PTC: nuclear enlargement, elongation, clearing, grooves, pseudoinclusions
  • No necrosis, no mitoses (or very rare)
  • RAS mutations (~30%) and THADA fusions - distinct from classic PTC (BRAF V600E)
• Clinical significance: Low risk of recurrence/metastasis (~1%) - allows conservative surgery (lobectomy) without RAI; avoids overtreatment
• Caveat: Any invasion (even focal) upgrades it to "invasive EFVPTC" = carcinoma

2. High-Grade Follicular Cell-Derived Carcinomas

• High-grade PTC: Conventional PTC histology + high mitotic rate (≥3/10 HPF) and/or necrosis (without dedifferentiation)
• High-grade FTC: Similarly defined
• These are BRAF or RAS mutated with additional TERT promoter mutations, TP53 - explaining aggressive behavior
• Intermediate prognosis between differentiated and anaplastic carcinoma

3. Differentiated High-Grade Thyroid Carcinoma (DHGTC)

• New entity distinct from poorly differentiated thyroid carcinoma (PDTC)
• Does NOT meet Turin criteria for PDTC (no insular growth, no solid/trabecular architecture required)
• Defined purely by mitotic activity ≥3/10 HPF and/or tumor necrosis in an otherwise differentiated carcinoma
• Clinically aggressive; TERT promoter mutations common

4. Papillary Thyroid Carcinoma - Expanded Molecular Subtyping

• BRAF V600E-like group: Classic PTC, tall cell variant, columnar cell variant - aggressive features, poor RAI response
• RAS-like group: Follicular variant PTC - indolent, good RAI response
• Fusions-driven (RTK-activating fusions): RET/PTC fusions (RET-CCDC6, RET-NCOA4), NTRK fusions, ALK fusions - targetable with TKIs (selpercatinib, larotrectinib)

5. Sclerosing Mucoepidermoid Carcinoma with Eosinophilia

• Rare, newly characterized thyroid carcinoma
• Associated with Hashimoto thyroiditis and eosinophilic infiltrate
• Distinct from other thyroid carcinomas; ESO1+ by IHC; p63+
• Indolent; associated with chromosomal translocation

6. Secretory Carcinoma of Thyroid (ETV6-NTRK3 fusion)

• Analogous to secretory carcinoma of breast and salivary gland
• ETV6-NTRK3 fusion - targetable with larotrectinib or entrectinib
• Newly recognized as a distinct primary thyroid carcinoma

7. Cribriform Morular Thyroid Carcinoma

• Previously called "cribriform-morular variant of PTC"
• WHO 2022 recognizes it as a distinct tumor type (not a PTC variant)
• Associated with familial adenomatous polyposis (FAP) / APC germline mutations
• Morular squamoid nests (nuclear beta-catenin expression), cribriform architecture
• TTF1 negative, ER/PR positive, nuclear beta-catenin positive

8. Thyroid Tumor Diagnostic Terminology Updates (Bethesda + WHO alignment)

• Hyalinizing trabecular tumor (HTT): GLIS3-GLIS1 fusions; reclassified from carcinoma to neoplasm of uncertain malignant potential (NUMP)
• Thyroid carcinoma showing thymus-like elements (CASTLE): Recognized as a distinct entity; CD5+, CD117+; indolent behavior

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Q.9 - Impact of 2021 WHO Classification on Diagnosis of CNS Tumors (7 marks)

Background

Key Principles of 2021 Classification

1. Integrated diagnosis: Combining histologic phenotype + molecular genotype into a single diagnosis
2. Molecular data can override histology when the two are discordant
3. Grading is now within tumor types (not across types) - CNS WHO grades 1-4
4. Arabic numerals used for grades (grade 2, not grade II)
5. New entities defined primarily by molecular criteria

Major Changes by Tumor Category

• TERT promoter mutation, AND/OR
• Whole chromosome 7 gain + chromosome 10 loss (+7/-10), AND/OR
• EGFR amplification

• Pilocytic astrocytoma: BRAF-KIAA1549 fusion (most common); or BRAF V600E; remains CNS WHO grade 1
• Pleomorphic xanthoastrocytoma (PXA): BRAF V600E (~65%); now formally included; targetable with vemurafenib/dabrafenib
• Astroblastoma, MN1-altered: New entity; MN1 rearrangement; predominantly affects young females

• NF2-mutant: Most common; grades 1-3
• TRAF7, KLF4, AKT1 (E17K), SMO: Benign, secretory/microcystic types
• TERT promoter, CDKN2A/B del: High-grade (grade 3); predict recurrence regardless of histology
• 2021 classification allows upgrading to grade 2 or 3 based on brain invasion + molecular data

• Primary CNS lymphoma (PCNSL): DLBCL, now under "Large B-cell lymphoma of immune-privileged sites" (includes vitreoretinal and testicular lymphoma) - reflecting shared pathobiology

• Intracranial mesenchymal non-meningothelial tumors: CIC-rearranged sarcoma, BCOR-altered neoplasms
• Hemangiopericytoma replaced by Solitary fibrous tumor (SFT) - NAB2-STAT6 fusion
• Ganglioglioma, BRAF V600E-mutant: High response to BRAF inhibitors

Impact on Clinical Practice

1. Improved prognostication: IDH status is the single most important prognostic marker for diffuse gliomas
2. Targeted therapy guidance: BRAF V600E (dabrafenib+trametinib), FGFR fusions (erdafitinib), NTRK fusions (larotrectinib), IDH mutations (vorasidenib - FDA approved 2024 for IDH-mutant grade 2 glioma)
3. Clinical trial stratification: Molecular subtypes define trial cohorts
4. Avoids misclassification: A histologically low-grade glioma with IDH-wildtype + TERT mutation + +7/-10 is classified as GBM grade 4 - preventing undertreatment
5. Pediatric-specific entities: Prevents applying adult treatment paradigms inappropriately

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• Robbins and Cotran Pathologic Basis of Disease, 10th Edition - Ovarian tumors, CNS tumors, Hematologic malignancies
• Robbins & Kumar Basic Pathology - Fallopian tube/STIC, CNS tumor classification
• Quick Compendium of Clinical Pathology, 5th ed. - Grey zone lymphoma, WHO-5/ICC classification
• Dermatology 2-Volume Set 5e - Chediak-Higashi Syndrome
• Fishman's Pulmonary Diseases and Disorders - PD-L1 expression
• Campbell Walsh Wein Urology - Bladder cancer molecular biology, immune checkpoint therapy
• Harrison's Principles of Internal Medicine 22E (2025) - CNS tumor WHO 2021, lung cancer molecular pathogenesis
• Tietz Textbook of Laboratory Medicine, 7th Edition - Liquid biopsy, ctDNA

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Quick Summary of What's Covered

• Draw the two-pathway model diagram for Q.6 (STIC)
• Include a table comparing IDH-mutant vs IDH-wildtype glioma for Q.9
• For Q.2, structure each sub-part (a, b, c, d) clearly with headers to maximize marks
• For Q.5, emphasize the WHO-5 name change and the CD30/CD20/CD15 immunophenotypic overlap