Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung malignancy characterized by rapid growth, early metastasis, and initial chemosensitivity followed by near-universal relapse. SCLC accounts for approximately 13-15% of lung cancers and is strongly associated with tobacco smoking. Molecularly, SCLC is defined by near-universal inactivation of both TP53 and RB1 tumor suppressors, leading to loss of cell cycle checkpoints and genomic instability. Unlike NSCLC, SCLC lacks actionable driver mutations and is treated primarily with chemotherapy plus immunotherapy. Despite high initial response rates, long-term survival remains poor.
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name: Small Cell Lung Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung malignancy
characterized by rapid growth, early metastasis, and initial chemosensitivity followed
by near-universal relapse. SCLC accounts for approximately 13-15% of lung cancers and
is strongly associated with tobacco smoking. Molecularly, SCLC is defined by near-universal
inactivation of both TP53 and RB1 tumor suppressors, leading to loss of cell cycle
checkpoints and genomic instability. Unlike NSCLC, SCLC lacks actionable driver mutations
and is treated primarily with chemotherapy plus immunotherapy. Despite high initial
response rates, long-term survival remains poor.
categories:
- Neuroendocrine Neoplasm
- Lung Cancer Subtype
- Solid Tumor
parents:
- lung neoplasm
has_subtypes:
- name: Limited-Stage SCLC
description: >-
Disease confined to one hemithorax that can be encompassed within a tolerable
radiation field. Approximately 30% of SCLC presents as limited-stage. Treatment
includes concurrent chemoradiation with potential for cure.
- name: Extensive-Stage SCLC
description: >-
Disease beyond a single hemithorax or with distant metastases. Approximately
70% of SCLC presents as extensive-stage. Treated with chemotherapy plus
immunotherapy; not curable but can achieve meaningful responses.
- name: SCLC-A (ASCL1-high)
description: >-
SCLC subtype defined by high ASCL1 expression. Associated with classic
neuroendocrine phenotype and may respond differently to therapy.
- name: SCLC-N (NEUROD1-high)
description: >-
SCLC subtype defined by high NEUROD1 expression. Variant neuroendocrine
phenotype.
- name: SCLC-P (POU2F3-high)
description: >-
SCLC subtype defined by high POU2F3 expression. Tuft cell-like phenotype,
may lack classic neuroendocrine markers.
- name: SCLC-Y (YAP1-high)
description: >-
SCLC subtype with YAP1 activation. Non-neuroendocrine phenotype, may arise
from epithelial-mesenchymal transition.
environmental:
- name: Tobacco Smoking
description: >-
Cigarette smoking is the dominant risk factor for SCLC, with a much stronger
association than for lung adenocarcinoma. Tobacco carcinogens drive widespread
genomic damage and contribute to TP53 and RB1 inactivation.
evidence:
- reference: PMID:8166467
reference_title: "Overview on small cell lung cancer in the world: industrialized countries, Third World, eastern Europe."
supports: SUPPORT
snippet: "Cigarette smoking and occupational risk factors are more strongly associated with squamous and small cell lung cancers than with adenocarcinoma."
explanation: "Supports the strong association between SCLC and cigarette smoking."
exposure_term:
preferred_term: exposure to tobacco smoking
term:
id: ECTO:6000029
label: exposure to tobacco smoking
pathophysiology:
- name: TP53 Inactivation
description: >-
TP53 is inactivated in >90% of SCLC through mutations, deletions, or both.
Loss of p53 function eliminates the G1/S checkpoint and apoptotic response
to DNA damage, enabling survival despite genomic instability.
evidence:
- reference: PMID:36399634
reference_title: "Retinoblastoma Expression and Targeting by CDK4/6 Inhibitors in Small Cell Lung Cancer."
supports: PARTIAL
snippet: 'The canonical model of "small cell lung cancer" (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1.'
explanation: "Abstract states the canonical model involves TP53 and RB1 inactivation."
cell_types:
- preferred_term: type II pneumocyte
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: DNA damage response, signal transduction by p53 class mediator
modifier: ABSENT
term:
id: GO:0030330
label: DNA damage response, signal transduction by p53 class mediator
downstream:
- target: Loss of Cell Cycle Checkpoints
description: Cells proliferate despite DNA damage
- name: RB1 Inactivation
description: >-
RB1 is inactivated in >90% of SCLC through mutations, deletions, or both.
Loss of Rb function eliminates the G1/S checkpoint by releasing E2F
transcription factors, enabling uncontrolled S-phase entry.
evidence:
- reference: PMID:36399634
reference_title: "Retinoblastoma Expression and Targeting by CDK4/6 Inhibitors in Small Cell Lung Cancer."
supports: PARTIAL
snippet: 'The canonical model of "small cell lung cancer" (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1.'
explanation: "Abstract states the canonical model involves TP53 and RB1 inactivation."
biological_processes:
- preferred_term: negative regulation of G1/S transition of mitotic cell cycle
modifier: ABSENT
term:
id: GO:2000134
label: negative regulation of G1/S transition of mitotic cell cycle
downstream:
- target: Loss of Cell Cycle Checkpoints
description: Uncontrolled cell cycle progression
- name: Loss of Cell Cycle Checkpoints
description: >-
Combined TP53 and RB1 loss eliminates major cell cycle checkpoints. Cells
proliferate rapidly without the normal restraints on replication. This
explains the rapid doubling time and initial chemosensitivity (dividing
cells are vulnerable to chemotherapy).
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: Genomic Instability
description: Accumulation of mutations and chromosomal alterations
- name: Genomic Instability
description: >-
Loss of TP53 and RB1 leads to widespread genomic instability with frequent
chromosomal gains and losses. Amplification of MYC family genes (MYC, MYCL,
MYCN) occurs in ~20% of SCLC and is associated with worse prognosis.
biological_processes:
- preferred_term: DNA repair
modifier: ABNORMAL
term:
id: GO:0006281
label: DNA repair
- name: Neuroendocrine Differentiation
description: >-
SCLC cells exhibit neuroendocrine differentiation, expressing markers such
as synaptophysin, chromogranin A, and CD56 (NCAM). Neuroendocrine phenotype
is regulated by lineage transcription factors (ASCL1, NEUROD1). Some SCLC
produces paraneoplastic hormones (ACTH, ADH).
biological_processes:
- preferred_term: neuron differentiation
modifier: ABNORMAL
term:
id: GO:0030182
label: neuron differentiation
- name: Functional Neuron-SCLC Synapses
description: >-
SCLC cells can form functional synapses with neurons and receive synaptic
transmission.
biological_processes:
- preferred_term: synapse assembly
modifier: ABNORMAL
term:
id: GO:0007416
label: synapse assembly
- preferred_term: chemical synaptic transmission
modifier: ABNORMAL
term:
id: GO:0007268
label: chemical synaptic transmission
evidence:
- reference: PMID:40931078
reference_title: "Functional synapses between neurons and small cell lung cancer."
supports: SUPPORT
snippet: "Here we show that SCLC cells can form functional synapses and receive synaptic transmission."
explanation: "Abstract reports functional synapses and synaptic transmission between neurons and SCLC cells."
- name: Neuron-Driven Proliferation
description: >-
SCLC cells gain a proliferation advantage when co-cultured with neurons.
biological_processes:
- preferred_term: positive regulation of cell population proliferation
modifier: INCREASED
term:
id: GO:0008284
label: positive regulation of cell population proliferation
evidence:
- reference: PMID:40931078
reference_title: "Functional synapses between neurons and small cell lung cancer."
supports: SUPPORT
snippet: "we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons."
explanation: "Abstract reports neuron co-culture provides a proliferation advantage to SCLC cells."
- name: Glutamate Signaling Dependency
description: >-
Inhibition of glutamate signaling has therapeutic efficacy in SCLC models,
implicating glutamatergic signaling in tumor growth.
biological_processes:
- preferred_term: glutamate receptor signaling pathway
modifier: ABNORMAL
term:
id: GO:0007215
label: glutamate receptor signaling pathway
- preferred_term: synaptic transmission, glutamatergic
modifier: ABNORMAL
term:
id: GO:0035249
label: synaptic transmission, glutamatergic
evidence:
- reference: PMID:40931078
reference_title: "Functional synapses between neurons and small cell lung cancer."
supports: SUPPORT
snippet: "Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC."
explanation: "Abstract reports therapeutic efficacy of glutamate signaling inhibition in an SCLC mouse model."
histopathology:
- name: Neuroendocrine Carcinoma
finding_term:
preferred_term: Neuroendocrine Carcinoma
term:
id: NCIT:C3773
label: Neuroendocrine Carcinoma
frequency: VERY_FREQUENT
description: Small-cell lung cancer is a very aggressive neuroendocrine carcinoma.
evidence:
- reference: PMID:24734358
reference_title: "[Role of surgery in small cell lung cancer]."
supports: SUPPORT
snippet: "Small-cell lung cancer (SCLC) is a \nvery aggressive neuroendocrine carcinoma"
explanation: Abstract defines SCLC as a very aggressive neuroendocrine carcinoma.
phenotypes:
- category: Neoplastic
name: Lung Neoplasm
frequency: OBLIGATE
description: >-
SCLC typically presents as a central/hilar mass with extensive mediastinal
lymphadenopathy. Peripheral nodules are rare.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
- category: Clinical
name: Smoking Association
frequency: VERY_FREQUENT
description: >-
SCLC is strongly associated with tobacco smoking, with >95% of patients
having smoking history. SCLC rarely occurs in never-smokers.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
- category: Clinical
name: Brain Metastases
frequency: VERY_FREQUENT
description: >-
Brain metastases are extremely common in SCLC, occurring in up to 50-80%
of patients during disease course. Prophylactic cranial irradiation (PCI)
may reduce this risk in responders.
phenotype_term:
preferred_term: Neoplasm of the nervous system
term:
id: HP:0004375
label: Neoplasm of the nervous system
- category: Clinical
name: Paraneoplastic Syndromes
frequency: OCCASIONAL
description: >-
SCLC commonly produces paraneoplastic syndromes including SIADH (hyponatremia),
Cushing syndrome (ectopic ACTH), Lambert-Eaton myasthenic syndrome (anti-VGCC
antibodies), and limbic encephalitis (anti-Hu antibodies).
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
biochemical:
- name: Neuroendocrine Markers
notes: >-
SCLC expresses neuroendocrine markers: synaptophysin, chromogranin A, and
CD56 (NCAM). At least one marker is typically positive. TTF-1 is also
frequently positive. Ki-67 proliferation index is typically very high (>50%).
evidence:
- reference: PMID:33687006
reference_title: "Clinicopathological and immunohistochemical study of pulmonary neuroendocrine tumors - A single-institute experience."
supports: PARTIAL
snippet: "markers which included synaptophysin, chromogranin, CD56"
explanation: "Pulmonary neuroendocrine tumor study notes diagnostic IHC panel includes classic neuroendocrine markers used for SCLC."
genetic:
- name: TP53
association: Somatic Inactivating Mutation
inheritance:
- name: Somatic
notes: >-
TP53 (17p13.1) is inactivated in >90% of SCLC through biallelic mutations
or deletions. Loss of p53 is considered a defining feature of SCLC.
Combined with RB1 loss, this creates the aggressive phenotype.
- name: RB1
association: Somatic Inactivating Mutation
inheritance:
- name: Somatic
notes: >-
RB1 (13q14.2) is inactivated in >90% of SCLC through biallelic mutations
or deletions. Combined TP53/RB1 loss is essentially universal in SCLC
and serves as a molecular definition of the disease.
- name: MYC
association: Amplification
inheritance:
- name: Somatic
notes: >-
MYC family amplification (MYC, MYCL, MYCN) occurs in ~20% of SCLC.
MYC amplification is associated with variant histology and worse prognosis.
May predict response to certain therapeutic approaches (Aurora kinase
inhibitors, chemotherapy timing).
- name: NOTCH
association: Somatic Inactivating Mutation
inheritance:
- name: Somatic
notes: >-
NOTCH family members (especially NOTCH1) are inactivated in ~25% of SCLC.
NOTCH normally suppresses neuroendocrine differentiation; its loss promotes
the neuroendocrine phenotype.
treatments:
- name: Platinum-Etoposide Chemotherapy
description: >-
Carboplatin or cisplatin plus etoposide is the backbone of SCLC treatment.
High initial response rates (60-80%) but nearly universal relapse. Four
cycles is standard for extensive-stage; concurrent with radiation for
limited-stage.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Atezolizumab (with Chemotherapy)
description: >-
PD-L1 checkpoint inhibitor added to carboplatin-etoposide for extensive-stage
SCLC. IMpower133 trial showed modest overall survival benefit. Now standard
first-line for extensive-stage.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: atezolizumab
term:
id: NCIT:C106250
label: Atezolizumab
- name: Durvalumab (with Chemotherapy)
description: >-
PD-L1 checkpoint inhibitor added to platinum-etoposide for extensive-stage
SCLC. CASPIAN trial showed overall survival benefit. Alternative to
atezolizumab-based regimen.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: durvalumab
term:
id: NCIT:C103194
label: Durvalumab
- name: Thoracic Radiation
description: >-
Concurrent thoracic radiation with chemotherapy for limited-stage SCLC.
Essential component of potentially curative therapy. Consolidative thoracic
radiation may also benefit select extensive-stage patients.
treatment_term:
preferred_term: radiation therapy
term:
id: MAXO:0000014
label: radiation therapy
- name: Prophylactic Cranial Irradiation
description: >-
Whole-brain radiation to prevent brain metastases in responding patients.
Reduces brain metastasis incidence but controversial due to neurocognitive
effects. Alternative is surveillance with MRI.
treatment_term:
preferred_term: radiation therapy
term:
id: MAXO:0000014
label: radiation therapy
- name: Lurbinectedin
description: >-
Transcription inhibitor approved for relapsed SCLC. Alternative to topotecan
for second-line treatment. Works by inhibiting oncogenic transcription
factors.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: lurbinectedin
term:
id: CHEBI:746908
label: lurbinectedin
- name: Topotecan
description: >-
Topoisomerase I inhibitor used for relapsed SCLC. Standard second-line
option, though responses are generally modest and short-lived.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: topotecan
term:
id: CHEBI:63632
label: topotecan
disease_term:
preferred_term: small cell lung carcinoma
term:
id: MONDO:0008433
label: small cell lung carcinoma
classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor