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Lung Tumors — WHO Classification, Etiopathogenesis & Morphology

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Overview

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WHO Classification (2021) — Malignant Epithelial Lung Tumors

Historic Subdivision (Clinically Important)

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Epidemiology

• Leading cause of cancer-related death in men AND women (since 1987) in high-resource countries
• ~237,000 new cases / ~130,000 deaths per year (USA, 2022)
• Peak incidence: 5th–6th decade

• 50% have distant metastases at diagnosis; 25% have regional nodal involvement

• 5-year survival: ~20% overall; ~50% if localized
• Adenocarcinoma has now replaced squamous cell carcinoma as the most common type — due to decline in tobacco use and rise in peripheral adenocarcinomas in women and never-smokers

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Etiopathogenesis

1. Tobacco Smoking (Most Important)

• 85% of lung carcinomas are attributable to smoking
• Squamous cell and small cell carcinomas have the strongest association
• Adenocarcinoma also associated, but less strongly
• Carcinogens in tobacco: polycyclic aromatic hydrocarbons, nitrosamines → cause TP53 mutations, KRAS mutations
• Risk: 20× higher in heavy smokers; dose-dependent; risk persists even after cessation
• Passive (secondhand) smoke also increases risk

2. Industrial/Occupational Carcinogens

3. Air Pollution

• Polycyclic hydrocarbons in polluted air — modest but real risk

4. Molecular/Genetic Alterations

5. Precursor Lesions (Stepwise Carcinogenesis)

• Squamous cell CA: Normal epithelium → squamous metaplasia → dysplasia → carcinoma in situ → invasive carcinoma (due to repeated tobacco carcinogen exposure)
• Adenocarcinoma: Atypical adenomatous hyperplasia (AAH) → Adenocarcinoma in situ (AIS, formerly BAC) → Minimally invasive adenocarcinoma → Invasive adenocarcinoma

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Morphology of Individual Types

1. Adenocarcinoma

• Gland-forming, papillary, micropapillary, or solid growth patterns
• Lepidic pattern (formerly BAC): tumor cells grow along pre-existing alveolar walls without stromal invasion — best prognosis
• Mucinous variant: columnar cells with mucin, grow along alveoli, produce "pneumonia-like" consolidation
• Clara cells or type II pneumocytes as cells of origin
• Mucin secretion (PAS/Alcian blue positive)
• IHC: TTF-1 positive, Napsin A positive, CK7 positive

2. Squamous Cell Carcinoma

• Sheets and nests of polygonal cells
• Keratin pearls (concentric whorls of keratin)
• Intercellular bridges (desmosomes)
• Individual cell keratinization (pink glassy cytoplasm)
• Moderately to well-differentiated tumors show classic squamous features
• IHC: p40 positive, p63 positive, CK5/6 positive

3. Small Cell Carcinoma (SCLC)

• Oat cell appearance: small (2× the size of lymphocyte), round-to-fusiform cells
• Scant cytoplasm
• Salt-and-pepper chromatin (finely granular, neuroendocrine pattern)
• No visible nucleoli
• Nuclear molding (nuclei indent each other)
• Abundant mitoses and geographic necrosis
• Azzopardi effect: DNA encrustation around vessel walls from necrotic tumor
• Arranged in sheets, ribbons, and nests
• IHC: Synaptophysin+, Chromogranin A+, CD56+, TTF-1 often positive; NSE positive
• Paraneoplastic syndromes are common: SIADH (ectopic ADH), Cushing's (ectopic ACTH), Eaton-Lambert syndrome (anti-VGCC antibodies)

4. Large Cell Carcinoma

• Large polygonal cells with abundant cytoplasm
• Prominent nucleoli, vesicular nuclei
• No keratin pearls, no gland formation
• IHC negative for squamous and adenocarcinoma markers
• Large cell neuroendocrine carcinoma (LCNEC): shows neuroendocrine morphology (organoid nesting, rosettes) + large cells; IHC: Synaptophysin+, Chromogranin+; very aggressive

5. Carcinoid Tumors

• Uniform cells arranged in nests, cords, and trabeculae (organoid pattern)
• Round nuclei with salt-and-pepper chromatin
• Scant to moderate cytoplasm
• No significant pleomorphism in typical carcinoid
• IHC: Chromogranin A+, Synaptophysin+, CD56+

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Secondary/Metastatic Lung Tumors

• The lung is the most common site of metastasis (hematogenous spread)
• Sources: breast, colon, kidney, uterus, prostate, stomach
• Pattern: multiple bilateral nodules ("cannonball metastases") vs. solitary nodule
• Lymphangitic carcinomatosis: tumor spread along lymphatics → miliary pattern, dyspnea

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Summary Table: Key Distinguishing Features

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Leukemia — Definition, Classification, and Detailed Pathology

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Definition

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Classification of Leukemia

By Maturity of Cells

By Cell Lineage

LEUKEMIA
├── MYELOID
│   ├── Acute Myeloid Leukemia (AML)
│   └── Chronic Myeloid Leukemia (CML)
└── LYMPHOID
    ├── Acute Lymphoblastic Leukemia (ALL)
    └── Chronic Lymphocytic Leukemia (CLL)

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I. CHRONIC MYELOID LEUKEMIA (CML)

Definition & Epidemiology

• Myeloproliferative neoplasm arising from a pluripotent hematopoietic stem cell
• Adults aged 25–60 years; peak: 4th–5th decade
• ~4,500 new cases/year (USA)

Etiopathogenesis

• Hallmark: Philadelphia chromosome (Ph¹) — present in >90% of cases
  • Reciprocal translocation t(9;22)(q34;q11)
  • Creates BCR::ABL1 fusion gene → encodes BCR-ABL tyrosine kinase (210 kDa)
  • BCR-ABL constitutively activates RAS and other pro-survival signals, making cells growth factor–independent
  • Does NOT block differentiation → cells proliferate AND mature (explains high WBC with mature cells)
• Remaining 5%: complex/cryptic rearrangements — detected by FISH or PCR

Peripheral Blood Smear (CML)

• Markedly elevated WBC — often >100,000/μL
• Entire spectrum of granulocytic maturation: myeloblasts, promyelocytes, myelocytes, metamyelocytes, band forms, mature neutrophils
• Basophilia and eosinophilia — characteristic; distinguishes from leukemoid reaction
• Thrombocytosis (platelets elevated)
• Anemia (normocytic normochromic)

Bone Marrow (CML)

• Hypercellular (markedly); virtual disappearance of fat spaces
• Increased granulocytic and megakaryocytic precursors
• Blasts <10% in chronic phase
• Leukocyte alkaline phosphatase (LAP) score: LOW (vs. high in leukemoid reaction — key differentiator)

Key Distinguishing Feature vs. Leukemoid Reaction

Phases of CML

1. Chronic phase (3–5 years): Mature granulocytes, <10% blasts
2. Accelerated phase: 10–19% blasts, increasing basophilia
3. Blast crisis: ≥20% blasts → transforms to AML (70%) or ALL (30%)

Treatment

• Imatinib (Gleevec) — BCR-ABL tyrosine kinase inhibitor; revolutionary targeted therapy

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II. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Definition & Epidemiology

• Neoplasm of mature CD5+ B cells (arrested at a stage of naive B-cell development)
• Most common leukemia of adults in the Western world
• Predominantly older adults; more common in men
• CLL and SLL (Small Lymphocytic Lymphoma) are the same disease:
  • CLL: peripheral blood lymphocytes >5,000/μL
  • SLL: predominantly lymph node involvement

Etiopathogenesis

• BCL-2 overexpression (from 13q deletion → loss of miRNA negative regulators) → inhibits apoptosis → tumor survival > proliferation
• BTK (Bruton Tyrosine Kinase) signaling via surface immunoglobulin (BCR) promotes growth/survival
• Immune dysregulation: hypogammaglobulinemia → susceptibility to infections
• 15% develop autoimmune hemolytic anemia (warm autoantibodies — made by non-malignant bystander B cells)

Peripheral Blood Smear (CLL)

• Absolute lymphocytosis (sustained >5,000/μL)
• Small, mature-appearing lymphocytes with:
  • Dark round nuclei
  • Condensed/clumped ("soccer ball") chromatin
  • Scant cytoplasm
  • No prominent nucleoli
• Smudge cells (basket cells) — pathognomonic: fragile leukemic lymphocytes crushed during smear preparation

Bone Marrow (CLL)

• Interstitial or nodular lymphocytic infiltration initially; later diffuse replacement
• Sheets of small lymphocytes identical to peripheral blood
• Residual hematopoietic elements reduced

Lymph Node (CLL/SLL)

• Diffuse effacement by small lymphocytes
• Proliferation centers (pseudofollicles) — pale foci of larger, actively dividing cells — pathognomonic for CLL/SLL

IHC: CD5+, CD19+, CD23+, CD20 (dim), surface Ig (dim)

Prognosis Markers

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III. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Definition & Epidemiology

• Neoplasm of immature lymphoid precursors (lymphoblasts) — pre-B or pre-T cells
• Most common cancer in children (peak: 3 years for B-ALL; adolescence for T-ALL)
• ~2,500 new cases/year in USA
• 85% are B-ALL (bone marrow/blood); 15% T-ALL (often thymic mass in adolescent males)

Etiopathogenesis

• Mutations in transcription factors essential for lymphoid development:
  • B-ALL: PAX5, TCF3, ETV6, RUNX1, BCR::ABL1 (poor prognosis), KMT2A (11q23)
  • T-ALL: NOTCH1 mutations (most common)
• Leads to maturation arrest + increased self-renewal
• Down syndrome: 10–20× increased risk of ALL (often B-ALL)
• Cytogenetic subtypes (prognostically important):

Peripheral Blood Smear (ALL)

• Variable WBC — may be low, normal, or high
• Lymphoblasts: medium-sized cells with:
  • High N:C ratio
  • Scant agranular pale-blue cytoplasm
  • Finely stippled/homogeneous chromatin ("immature" pattern)
  • Nucleoli present (1–2, inconspicuous to prominent)
  • Round/oval or convoluted nuclei (T-ALL)
• Anemia (normocytic), thrombocytopenia

Bone Marrow (ALL)

• Hypercellular with diffuse replacement by lymphoblasts
• ≥20% lymphoblasts (often 80–100%)
• Suppression of all normal hematopoietic lineages

IHC/Immunophenotype

• TdT (Terminal deoxynucleotidyl Transferase) positive — hallmark of ALL (marks lymphoid immaturity); negative in AML
• B-ALL: CD10+, CD19+, CD20 (variable)
• T-ALL: CD2+, CD3+, CD5+, CD7+, CD4/CD8 double positive (thymic stage)

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IV. ACUTE MYELOID LEUKEMIA (AML)

Definition & Epidemiology

• Neoplasm of immature myeloid progenitors (myeloblasts) — impaired differentiation → accumulation of blasts in marrow
• Incidence rises with age; peak after 60 years; also occurs in children
• ~13,000 new cases/year in USA

Etiopathogenesis — Driver Mutations (4 categories)

1. Transcription factor mutations (most important):
   • t(8;21) → RUNX1::RUNX1T1 — blocks myeloid differentiation
   • inv(16) → CBFB::MYH11 — same pathway
   • t(15;17) → PML::RARA — Acute Promyelocytic Leukemia (APL/AML-M3); ATRA therapy blocks this fusion protein → differentiation induced
2. Growth factor/RAS signaling mutations: FLT3 (ITD — poor prognosis), RAS, KIT
3. Epigenetic regulator mutations: DNMT3A, TET2, IDH1/2
4. Tumor suppressor mutations: TP53, NPM1

WHO Classification of AML (2022) — Simplified

FAB Classification of AML (French-American-British, 1976)

Auer Rods — pathognomonic of AML (never in ALL). Pink needle-like crystalline inclusions in the cytoplasm of blasts. Composed of fused azurophilic granules (condensed MPO). Especially prominent and numerous in APL (M3) — "faggot cells."

Peripheral Blood Smear (AML)

• Myeloblasts with:
  • Large cells, moderate to abundant cytoplasm
  • Fine/open chromatin
  • Prominent nucleoli (2–5) — key feature
  • Auer rods (M1, M2, M3) — pathognomonic
  • Cytoplasmic azurophilic granules
• Anemia, thrombocytopenia, neutropenia
• WBC variable (may be high, normal, or low — "aleukemic leukemia")

Bone Marrow (AML)

• Hypercellular; virtual replacement by myeloblasts
• ≥20% blasts required for AML diagnosis (WHO)
• Auer rods in blasts
• Suppression of normal erythroid, megakaryocytic, and lymphoid elements

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Cytochemical Stains (Acute Leukemia Diagnosis)

Key mnemonic: "MPO/SBB = Myeloid; PAS blocks + TdT = Lymphoid"

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Laboratory Findings Summary Table

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