What is the difference between small cell (small cell carcinoma) and non-small cell (non-small cell carcinoma) lung cancer?

Difference Between Small Cell and Non-Small Cell Lung Cancer

Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) differ fundamentally in their cellular characteristics, clinical behavior, prognosis, and treatment approaches—distinctions that remain critically important despite advances in lung cancer subtyping. 1

Key Clinical and Biological Differences

Epidemiology and Presentation

• SCLC comprises only 14% of all lung cancers but behaves far more aggressively, with nearly all patients presenting with advanced-stage disseminated disease at diagnosis. 1

• NSCLC represents more than 80% of lung cancer cases and includes adenocarcinoma (40%), squamous cell carcinoma (30%), and large cell carcinoma (5-10%). 2

• SCLC patients are almost universally heavy smokers (95% have tobacco use history), typically presenting with a perihilar mass causing peribronchial compression and obstruction. 1, 3

• Approximately 66-70% of SCLC patients have metastatic disease at diagnosis, compared to NSCLC which more commonly presents in earlier, potentially resectable stages. 4, 2

Cellular and Morphologic Characteristics

SCLC features distinctly small cells:

• Cells are 2-3 times the size of small lymphocytes with scant cytoplasm and high nuclear-to-cytoplasmic ratio. 1
• Nuclear molding, finely granular chromatin, and absent or inconspicuous nucleoli are characteristic. 1
• High mitotic activity with extensive necrosis and chromatic basophilic smearing. 1
• Crush artifact and perivascular basophilic condensation (Azzopardi effect) are commonly seen. 1
• Growth pattern shows large sheets with vague organoid nesting, ribbon-like patterns, and rosettes. 1

NSCLC features larger tumor cells:

• Cells are generally larger with moderate amounts of cytoplasm, vesicular or coarse chromatin pattern, and prominent nucleoli. 1
• Nuclear molding and smearing are typically absent. 1
• Glandular differentiation (adenocarcinoma) or squamous differentiation (intercellular bridges, keratinization, keratin pearls) helps identify NSCLC subtypes. 1, 4

Neuroendocrine Features

• SCLC is a high-grade neuroendocrine carcinoma derived from endogenous, endodermally derived neuroendocrine cells with dense-core neurosecretory granules containing bioactive amines and peptides. 1

• These neurosecretory granules are the source of paraneoplastic syndromes more common in SCLC, including Lambert-Eaton syndrome, paraneoplastic encephalomyelitis, sensory neuropathy, and syndrome of inappropriate ADH secretion. 4

Proliferation Rates

• SCLC demonstrates a markedly higher growth fraction index of 79 ± 10% compared to adenocarcinoma (38 ± 16%), squamous cell carcinoma (33 ± 15%), and large cell carcinoma (40 ± 18%). 5

• Ki-67 proliferation index in SCLC ranges from 50-70%, substantially higher than carcinoid tumors (5-15%), which helps distinguish these neuroendocrine tumor types. 1

Diagnostic Approach

Distinguishing SCLC from NSCLC is recommended for all parenchymal-based tumors, as this distinction fundamentally determines therapeutic approach and prognosis. 1

• Routine morphologic examination achieves differentiation in most cases with interobserver agreement exceeding 95% when standard criteria are met. 1

• For challenging cases, immunohistochemical panels are recommended to increase diagnostic accuracy (Grade 1B recommendation). 1

• Immunohistochemistry can identify TTF-1 and neuroendocrine markers in SCLC, while NSCLC shows positivity for napsin A (adenocarcinoma) or p63 (squamous cell carcinoma). 1, 4

Important Diagnostic Pitfall

• Combined SCLC exists where at least 10% of the tumor shows NSCLC features (large cell carcinoma, adenocarcinoma, or squamous cell carcinoma), which is particularly problematic in small tissue samples. 1

Prognostic and Therapeutic Implications

• The separation between SCLC and NSCLC underscores major differences in clinical presentation, behavior, prognosis, and therapeutic approaches. 1

• SCLC has a 5-year overall survival of only 12-30% with median survival for extensive-stage disease of approximately 12-13 months despite initial response rates of 60-70% to chemotherapy. 3

• SCLC initially responds well to chemotherapy but rapidly develops resistance, demonstrating high tumor plasticity and adaptability. 6

• NSCLC generally has better prognosis than SCLC, particularly when diagnosed at earlier stages amenable to surgical resection. 4