Describe clinical features, morphology , diagnostic approach in lung tumours

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Lung Tumours: Clinical Features, Morphology, and Diagnostic Approach

1. Epidemiology and Overview

Lung cancer is the most frequently diagnosed major cancer and the leading cause of cancer mortality worldwide. Globally in 2022, an estimated 2.5 million new cases were diagnosed with 1.8 million deaths. It is generally a disease of older adults (peak incidence 65-74 years), and each year kills more people than colon, breast, and prostate cancer combined.

Of all lung tumours:

90-95% are carcinomas
~5% are carcinoid tumours
2-5% are mesenchymal and other miscellaneous neoplasms

2. WHO Classification of Lung Tumours (2015)

Category	Subtypes
Adenocarcinoma	Lepidic, Acinar, Papillary, Micropapillary, Solid, Invasive mucinous, Colloid, Fetal, Enteric, AIS, Minimally invasive
Squamous cell carcinoma	Keratinizing, Nonkeratinizing, Basaloid, SCC in situ
Neuroendocrine tumours	Small cell carcinoma, Large cell neuroendocrine carcinoma, Carcinoid, DIPNECH
Large cell carcinoma	-
Other	Adenosquamous, Sarcomatoid, Salivary gland-type, Papillomas, Adenomas, Mesenchymal, Lymphohistiocytic

The three most common histologic subtypes - adenocarcinoma, squamous cell carcinoma, and small cell carcinoma - together account for approximately 85% of all lung cancer cases.

The historically important clinical distinction is SCLC vs NSCLC, because SCLC almost always presents at advanced (metastatic) stage and is best managed with chemotherapy, rarely surgery. More precise NSCLC subclassification has become critical due to targeted therapies.

3. Etiology and Risk Factors

Cigarette smoking: ~80% of lung cancers; risk is 60x greater in heavy smokers (2 packs/day for 20 years) vs non-smokers. Almost all SCLCs are smoking-related. Adenocarcinoma is the most common subtype in both smokers and non-smokers.
Secondhand smoke: ~3,000 non-smoking adult deaths/year in the US
Industrial hazards: Asbestos (synergistic with smoking for mesothelioma and lung carcinoma), uranium, radon, polycyclic aromatic hydrocarbons, nickel, chromium
Genetic factors: P-450 monooxygenase variants, DNA repair gene variants, driver mutations (EGFR, ALK, ROS1, KRAS, MET)
Air pollution: Outdoor and indoor pollution (radon in homes)

4. Clinical Features

Local / Regional Symptoms

Symptom	Mechanism
Cough	Bronchial irritation/obstruction
Hemoptysis	Mucosal invasion
Wheezing / stridor	Partial airway obstruction
Dyspnea	Obstruction, effusion, atelectasis
Post-obstructive pneumonia	Impaired drainage, recurrent infections
Chest pain	Pleural/chest wall invasion

Superior Sulcus (Pancoast) Tumour

Apical tumours invading neural structures around the trachea, including the cervical sympathetic plexus, produce:

Severe pain in the ulnar nerve distribution
Horner syndrome (enophthalmos, ptosis, miosis, anhidrosis) ipsilaterally

Superior Vena Cava Syndrome

Compression or invasion of the SVC causes:

Venous congestion and oedema of the head, neck, and arms
Ultimately, circulatory compromise

Metastatic Spread

Common sites: regional lymph nodes, adrenals, liver, brain, bone, kidney, contralateral lung.

5. Paraneoplastic Syndromes

Particularly common with SCLC (a neuroendocrine tumour). Key syndromes:

Syndrome	Mediator	Tumour Type
SIADH (hyponatraemia)	Ectopic ADH/vasopressin	SCLC, squamous
Cushing syndrome	Ectopic ACTH (POMC)	SCLC, bronchial carcinoid, adenocarcinoma
Hypercalcaemia	PTHrP	Squamous cell carcinoma
Lambert-Eaton myasthenic syndrome	Autoantibodies vs. presynaptic Ca²⁺ channels	SCLC
Peripheral neuropathy	Paraneoplastic antibodies	SCLC
Hypertrophic pulmonary osteoarthropathy	Unknown	Various (clubbing of fingers)
Acanthosis nigricans	-	Various
Trousseau syndrome	Hypercoagulable state	Various
Leukemoid reaction	Haematologic	Various

In ectopic ACTH production, hormone is unregulated (lacks normal feedback control) and may be incompletely processed (large POMC precursor released).

6. Morphology of Major Subtypes

Pathology of lung carcinomas - gross and histology

Fig. 15.34 (Robbins, Cotran & Kumar): (A) Lung adenocarcinoma with central scarring, anthracotic pigments, and pleural puckering. (B) Gland-forming adenocarcinoma with TTF-1 positivity (inset). (C) Squamous cell carcinoma as a central hilar mass. (D) Well-differentiated SCC with keratin pearls and intercellular bridges. (E) Large cell carcinoma, sheets of undifferentiated large cells. (F) Small cell carcinoma with basophilic cells and necrosis.

A. Adenocarcinoma (~40% of all lung cancers)

Location: Peripheral lung parenchyma, arises from terminal respiratory unit (acinus).

Precursor lesion: Atypical adenomatous hyperplasia → adenocarcinoma in situ (AIS) → minimally invasive → invasive.

Gross morphology:

Peripheral grey-white mass, often with pleural puckering due to desmoplastic fibrosis
Central scar with anthracotic pigments characteristic

Histology:

Gland-forming (acinar), papillary, micropapillary, solid, or lepidic patterns
Lepidic growth: tumour cells spread along pre-existing alveolar walls without stromal invasion - the only truly non-invasive pattern
AIS (formerly bronchioloalveolar carcinoma): ≤3 cm, pure lepidic growth, no stromal, vascular, or pleural invasion
Mucin production common

Immunohistochemistry (IHC):

TTF-1 (thyroid transcription factor-1) positive - highly characteristic
CK7 positive
Napsin A positive

Molecular markers: EGFR mutations (most common targetable mutation), ALK rearrangements, ROS1, KRAS, MET amplification

B. Squamous Cell Carcinoma (~25-30%)

Location: Central (hilar), arises from large bronchi.

Precursor lesion: Squamous metaplasia → dysplasia → carcinoma in situ → invasive (best-documented sequence).

Gross morphology:

Central / hilar mass, often bulky
Cavitation common (central necrosis)
Extends into bronchial lumen, causing obstruction

Histology:

Keratinization: keratin pearls (whorls of eosinophilic keratin), individual cell keratinization
Intercellular bridges (desmosomes) between cells
Basaloid variant: smaller cells, peripheral palisading
Nonkeratinizing variant: lacks obvious keratin but shows squamoid cytology

IHC:

p40 / p63 positive (squamous markers)
CK5/6 positive
TTF-1 negative

Molecular: PTHrP production (hypercalcaemia), FGFR1 amplification, DDR2 mutations

C. Small Cell Carcinoma (SCLC, ~15%)

Location: Usually central, arising near large bronchi.

Gross morphology:

Soft, white-grey perihilar/central mass
Extensive mediastinal involvement is characteristic
Areas of haemorrhage and necrosis

Histology - highly distinctive:

Small cells (slightly larger than lymphocytes), scant cytoplasm
"Oat cell" appearance: oval/fusiform, moulded cells
Finely granular "salt-and-pepper" chromatin (neuroendocrine chromatin pattern)
Absent or inconspicuous nucleoli
Nuclear moulding
Extensive necrosis
Azzopardi effect: basophilic encrustation of vascular walls by DNA from necrotic tumour cells (pathognomonic finding)
High mitotic rate
Combined SCLC: SCLC mixed with NSCLC elements (large cell neuroendocrine carcinoma or spindle cell morphology)

IHC:

Synaptophysin, chromogranin, CD56 positive (neuroendocrine markers)
TTF-1 positive (~90%)
Ki-67 very high (>50-80%)
Dot-like perinuclear CAM5.2 staining

D. Large Cell Carcinoma (~5-10%)

A diagnosis of exclusion - undifferentiated carcinoma without squamous, glandular, or neuroendocrine features on light microscopy.

Histology:

Sheets of large, pleomorphic cells
Prominent nucleoli
Abundant cytoplasm
No gland formation, keratinization, or neuroendocrine features

Large Cell Neuroendocrine Carcinoma (LCNEC):

Large cell morphology WITH neuroendocrine architecture (organoid nesting, palisading, rosettes, trabeculae)
IHC: neuroendocrine markers positive
High mitotic rate (>10/2mm²)
Behaves aggressively, similar to SCLC

E. Carcinoid Tumours (1-5%)

Occur in younger patients (<60 years), equal sex incidence
Not associated with smoking
Arise from neuroendocrine cells (Kulchitsky cells)
Typical carcinoid: low-grade, central, uniform round cells with stippled chromatin, organoid pattern
Atypical carcinoid: intermediate grade, 2-10 mitoses/2mm², necrosis
May produce carcinoid syndrome (serotonin, bradykinin)
IHC: synaptophysin, chromogranin, CD56 positive

7. Secondary Pathology of Lung Carcinoma

Partial obstruction: focal emphysema
Total obstruction: atelectasis
Impaired drainage: bronchitis, bronchiectasis, pulmonary abscess
Pleural extension: pleuritis, malignant effusions
Pericardial extension: pericarditis, tamponade
Lymphatic blockage: lymphangitis carcinomatosis

8. Staging

TNM staging (AJCC/UICC 8th edition) applies to lung carcinomas:

Stage	Description
Stage I	Localised tumour, no nodal involvement
Stage II	Nodal involvement (hilar/ipsilateral)
Stage III	Extensive nodal/mediastinal involvement (unresectable)
Stage IV	Distant metastases

Note: SCLC is traditionally staged as limited disease (confined to one hemithorax, treatable within a single radiation port) vs extensive disease (spread beyond one hemithorax, including malignant pleural/pericardial effusion).

9. Diagnostic Approach

Step 1 - Clinical Assessment

Symptoms (cough, haemoptysis, weight loss, dyspnoea, pain)
Risk factors (smoking history in pack-years, occupational/environmental exposure)
Signs of local invasion (SVC syndrome, Horner's, Pancoast)
Paraneoplastic manifestations

Step 2 - Imaging

Modality	Use
Chest X-ray	Initial screen; central mass, hilar enlargement, atelectasis, pleural effusion
CT chest/abdomen/pelvis	Tumour size, location, mediastinal and nodal involvement, adrenal/liver mets
PET-CT	Metabolic staging, detects occult metastases, guides biopsy
MRI brain	Brain metastases (especially SCLC, adenocarcinoma)
CT-guided needle biopsy	Peripheral lesions

Step 3 - Tissue Sampling

Method	Best For
Bronchoscopy + BAL/brushings/biopsy	Central tumours, endobronchial disease
EBUS-TBNA (Endobronchial ultrasound-guided transbronchial needle aspiration)	Mediastinal/hilar lymph nodes, central masses
CT-guided core needle biopsy	Peripheral lesions
Sputum cytology	Squamous cell carcinoma (orange-staining keratinised cells)
Thoracentesis / pleural biopsy	Malignant effusions
Surgical resection / VATS wedge	Peripheral nodules, definitive staging

Rapid on-site evaluation (ROSE) of FNA samples is standard practice to ensure adequacy and guide real-time sample handling.

Step 4 - Histopathological Evaluation

The main objective is histologic and molecular classification:

H&E morphology: Identify gland formation (adenocarcinoma), keratinisation (SCC), small cell features, or undifferentiated large cells
IHC panel for NSCLC subtyping:

Marker	Positive in	Negative in
TTF-1	Adenocarcinoma, SCLC	SCC
p40 / p63	Squamous cell carcinoma	Adenocarcinoma
CK7	Adenocarcinoma	SCC (usually)
CK5/6	Squamous	Adenocarcinoma
Synaptophysin / Chromogranin / CD56	SCLC, LCNEC, Carcinoid	Non-neuroendocrine
Ki-67	High in SCLC (>50%)	Low in typical carcinoid (<5%)
Napsin A	Adenocarcinoma	-

Molecular/Biomarker testing (mandatory in NSCLC):

Biomarker	Significance	Targeted Therapy
EGFR mutation	Mostly adenocarcinoma	Erlotinib, Osimertinib
ALK rearrangement	Adenocarcinoma, non-smokers	Crizotinib, Alectinib
ROS1 rearrangement	Adenocarcinoma	Crizotinib
KRAS G12C	Adenocarcinoma	Sotorasib, Adagrasib
MET exon 14 skipping	Adenocarcinoma	Tepotinib, Capmatinib
PD-L1 expression	All NSCLC	Pembrolizumab (immunotherapy)
BRAF V600E	Adenocarcinoma	Dabrafenib + Trametinib

Liquid biopsy (ctDNA): Used when tissue is insufficient, for monitoring, and resistance mutation detection

Step 5 - Final Integrated Diagnosis

A modern lung cancer diagnosis includes:

Histologic subtype (e.g., adenocarcinoma, lepidic-predominant)
Pathologic stage (pTNM)
Molecular profile (EGFR/ALK/ROS1/KRAS/PD-L1 status)
Resection margin status (if surgical specimen)
Treatment response assessment (if post-neoadjuvant)

10. Key Differentiating Features at a Glance

Feature	Adenocarcinoma	SCC	SCLC	Carcinoid
Location	Peripheral	Central	Central	Central
Smoking link	Both (highest in non-smokers)	Strong	Almost all	None
Gross	Grey-white peripheral mass, scar	Central cavitating mass	Central, necrotic	Polypoid bronchial
Histology	Glands, lepidic, TTF-1+	Keratin pearls, bridges, p40+	Oat cells, Azzopardi, synaptophysin+	Uniform cells, organoid
Paraneoplastic	PTHrP (rare)	PTHrP, hypercalcaemia	ACTH, SIADH, Lambert-Eaton	Carcinoid syndrome
Prognosis	Variable (stage/mutation)	Better if early, central	Worst overall	Best (typical)

Sources:

Robbins, Cotran & Kumar - Pathologic Basis of Disease, pp. 667-674
Murray & Nadel's Textbook of Respiratory Medicine, Chapter 22
Harrison's Principles of Internal Medicine, 22e - Chapter 98 (Paraneoplastic Syndromes)
Robbins & Kumar Basic Pathology

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