Lung Cancer

Quick Answer

FDG-PET/CT is central to lung cancer: it characterizes the solitary pulmonary nodule (FDG-avid nodules carry higher malignancy risk), stages nodal and distant disease more accurately than CT alone (upstaging occult mediastinal N2/N3 and distant metastases and preventing futile surgery), and restages after therapy. A PET-positive mediastinal node should generally be confirmed pathologically before it denies a patient curative surgery. Brain metastases need MRI — high cortical FDG makes PET insensitive there.

Definition

Lung cancer is a malignant epithelial neoplasm arising from the airways or alveolar epithelium. It is divided into non-small-cell lung cancer (NSCLC) — adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma (~85%) — and small-cell lung cancer (SCLC) (~15%), a high-grade neuroendocrine carcinoma. Pulmonary carcinoid tumors are separate, well-differentiated neuroendocrine neoplasms with distinct (SSTR-based) imaging.

Synonyms

Bronchogenic carcinoma; NSCLC / SCLC; adenocarcinoma, squamous cell carcinoma, large-cell carcinoma; bronchial carcinoid (typical/atypical).

Epidemiology

Lung cancer is the leading cause of cancer death worldwide. Tobacco smoking is the dominant cause and correlates with squamous and small-cell histology; adenocarcinoma is now the most common subtype and predominates among never-smokers. Incidence and histology vary by sex, region, and smoking prevalence, and low-dose CT screening of high-risk smokers shifts detection toward earlier stage.

Etiology & Risk Factors

• Tobacco (dose- and duration-dependent; the strongest cause).
• Radon, asbestos (synergistic with smoking), arsenic, and other occupational carcinogens.
• Air pollution, prior thoracic radiation, and pulmonary fibrosis (IPF).
• Family history and inherited susceptibility; EGFR-mutant disease clusters in never-smokers, women, and East Asian populations.

Pathophysiology

Chronic carcinogen exposure drives field cancerization and stepwise genomic damage. Adenocarcinomas are frequently driven by targetable oncogenic drivers (see below). SCLC is a highly proliferative neuroendocrine carcinoma with near-universal TP53 and RB1 loss and early dissemination. Paraneoplastic phenomena reflect ectopic secretion or autoimmunity: SIADH and Cushing with SCLC, hypercalcemia (PTHrP) with squamous carcinoma, and Lambert–Eaton myasthenic syndrome with SCLC.

Genetics & Molecular Biology

• NSCLC (adenocarcinoma) drivers: EGFR, ALK and ROS1 fusions, KRAS (G12C), BRAF, MET exon-14, RET, NTRK, HER2 — most with matched targeted therapies.
• PD-L1 expression and tumor mutational burden guide immunotherapy.
• SCLC: TP53/RB1 loss; DLL3 surface expression is an emerging theranostic/therapeutic target (bispecifics and radioligands under study).
• Pulmonary carcinoid: somatostatin-receptor (SSTR) expression underpins DOTATATE imaging and PRRT.

Histopathology

• Adenocarcinoma: glandular/lepidic growth; TTF-1 and napsin-A positive; ranges from indolent lepidic (former "BAC") to invasive.
• Squamous cell carcinoma: keratinization/intercellular bridges; p40/p63 positive; often central.
• Large-cell carcinoma: undifferentiated NSCLC of exclusion.
• SCLC: small cells, scant cytoplasm, high mitotic rate and Ki-67, neuroendocrine markers (synaptophysin, chromogranin, INSM1).
• Carcinoid: typical vs atypical (by mitoses/necrosis); SSTR-positive.

Clinical Presentation

Cough, hemoptysis, dyspnea, chest pain, recurrent pneumonia, and constitutional symptoms. Pancoast (superior sulcus) tumors cause shoulder/arm pain, Horner syndrome, and brachial-plexus signs. SVC syndrome with mediastinal disease. Paraneoplastic syndromes may precede the diagnosis. Many nodules are found incidentally or by screening while asymptomatic.

Laboratory Findings

No specific serum marker. Essential work-up in advanced NSCLC is molecular profiling (EGFR/ALK/ROS1/KRAS/BRAF/MET/RET/NTRK) and PD-L1; SCLC may show paraneoplastic biochemical signatures (hyponatremia, hypercortisolism).

Imaging Findings by Modality

• Chest radiograph: initial detection; insensitive for small/central disease.
• CT (incl. low-dose screening): nodule morphology (spiculation, size, growth), solid vs subsolid; staging anatomy.
• FDG-PET/CT: characterizes indeterminate nodules, stages nodes/distant disease, and restages — the single most impactful modality.
• MRI: brain metastases (PET insensitive), Pancoast/brachial-plexus and chest-wall invasion, and adrenal characterization.
• Bone scan: largely replaced by FDG-PET for osseous staging.

Solitary Pulmonary Nodule — Quantifying Risk

FDG avidity shifts the pretest probability of malignancy for an indeterminate solid nodule: an intensely avid nodule is more likely malignant and warrants tissue sampling, while a non-avid solid nodule above the partial-volume limit (~8–10 mm) has low malignancy risk and can often be followed. Below that size, low uptake is not reassuring (partial-volume effect), and subsolid/ground-glass, low-grade adenocarcinoma, and carcinoid can be genuinely FDG-poor.

Radiopharmaceutical Uptake Mechanisms

FDG reflects tumor glucose metabolism (GLUT/hexokinase), high in most NSCLC and SCLC but variable/low in carcinoid and lepidic adenocarcinoma. DOTATATE binds SSTR2 on well-differentiated carcinoid. Bone diphosphonates mark osteoblastic reaction (indirect).

Typical PET Tracers

Typical SPECT Tracers

• Quantitative V/Q (Tc-99m-MAA) — predicts postoperative lung function (predicted post-op FEV₁/DLCO) before resection.
• (Historical) Tc-99m-MDP bone scan for osseous metastases.

Therapy Indications

• Early NSCLC: surgical resection or SBRT (medically inoperable); (neo)adjuvant chemo-immunotherapy in selected stages.
• Locally advanced NSCLC: concurrent chemoradiation with consolidation immunotherapy.
• Advanced NSCLC: targeted therapy by driver mutation, immunotherapy by PD-L1, and chemotherapy.
• SCLC: platinum-etoposide plus immunotherapy ± thoracic/prophylactic cranial radiation.
• Metastatic pulmonary carcinoid (SSTR+): somatostatin analogs and ¹⁷⁷Lu-DOTATATE PRRT.

Theranostics

Two lung theranostic threads: SSTR-directed PRRT for metastatic well-differentiated pulmonary carcinoid (DOTATATE image → Lu-177-DOTATATE treat), and the emerging DLL3-targeted approaches in SCLC (imaging/therapy pairs and bispecifics under investigation). Quantitative V/Q functions as a "theranostic-adjacent" planning tool — predicting the functional cost of resection.

Differential Diagnosis

• Granulomatous disease (sarcoidosis, tuberculosis, histoplasmosis, other fungal) and infection/abscess — classic FDG-avid malignancy mimics, especially in the mediastinum.
• Rheumatoid nodules, organizing pneumonia, and hamartoma (fat/popcorn calcification on CT).
• Metastasis to the lung from an extrathoracic primary.

Reporting Checklist

• Nodule size, morphology (solid/subsolid), and SUVmax; state the partial-volume caveat for small nodules.
• TNM (8th edition) assignment; explicitly flag PET-positive N2/N3 as needing pathologic confirmation.
• Distant sites and second primaries; recommend brain MRI for staging when appropriate.
• Post-therapy caveats (radiation pneumonitis, atelectasis, immunotherapy-related uptake).

Prognosis

Stage is the dominant determinant (TNM 8th edition). Early, resectable NSCLC has favorable survival; N2/N3 and distant disease worsen it markedly. Driver-matched targeted therapy and immunotherapy have improved advanced-NSCLC outcomes. SCLC is chemo-sensitive but relapses early with a poorer prognosis. Metabolic parameters (SUVmax, metabolic tumor volume) carry independent prognostic weight.

Board Pearls

A PET-positive mediastinal node should generally be confirmed pathologically (EBUS/EUS or mediastinoscopy) before it denies a patient curative surgery — granulomatous and reactive nodes cause false positives, and mis-staging costs a resectable cure. PET's greatest value is catching occult distant metastases and second primaries that convert intent from curative to palliative (futility-reducing evidence: PLUS, Fischer).

FDG-low does not mean benign: carcinoid, lepidic/low-grade adenocarcinoma, and subsolid nodules can be poorly avid, and small nodules suffer partial-volume underestimation.

Brain metastases require MRI — intense physiologic cortical FDG makes PET insensitive for cerebral disease, so brain imaging is a separate staging step. For metastatic pulmonary carcinoid, switch tracers: DOTATATE (not FDG) selects SSTR-positive disease for ¹⁷⁷Lu-DOTATATE PRRT, while FDG-avid atypical/high-grade neuroendocrine disease behaves more aggressively.

Related Pages

• Tracer: FDG and DOTATATE (SSTR imaging for carcinoid).
• Disease: Neuroendocrine tumors (carcinoid PRRT pathway).
• Pitfalls: Incidental findings on FDG-PET, Pearls, pitfalls & normal variants.

Figure / Diagram Suggestions

• A nodule risk schematic: size vs FDG avidity vs subsolid morphology → malignancy probability.
• TNM 8th-edition nodal-station map with the "confirm N2/N3 pathologically" rule annotated.
• Dual-tracer NSCLC (FDG) vs carcinoid (DOTATATE) comparison plate.

Common Pitfalls

• Talc pleurodesis produces intense, often nodular pleural FDG uptake that persists for years and mimics malignant pleural disease — correlate with the CT (high-attenuation talc deposits) and pleurodesis history.
• Brown fat and muscle uptake in the neck and supraclavicular fossae can simulate N3 nodal disease — check the fused CT for a nodal correlate.
• Hyperglycemia and recent insulin shift FDG into muscle and degrade tumor conspicuity, risking a false-negative read of an otherwise avid tumor.
• A small FDG-avid adrenal nodule is not automatically a metastasis (adenomas can be mildly avid) — characterize with CT washout or MRI before upstaging to M1.

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