Small cell lung cancer is the most aggressive form of lung cancer and has the highest association with smoking of all lung cancers. Small cell lung cancer usually develops in the bronchi and expands through the bronchial mucosa. Small cell lung cancer often metastasizes rapidly to other parts of the body, including the brain, liver, and bone. A mutation in the p53 gene is reported in 75%-100% of the cases. Other molecular abnormalities that contribute to the development of small cell lung cancer have been described.

• A mutation in the p53 gene is reported in 75 – 100% of the cases of small cell lung cancer.
• Other molecular abnormalities that contribute to the development of small cell lung cancer are:^[1]
  • Chromosome 3p deletion (in 90% of cases)
  • MYC amplification (in 30% of cases)
  • BCL2 expression (in 95% of cases)
  • GRP (gastrin-releasing peptide) expression
  • RB1 deletion (loss of RB1 protein)
  • VEGF (vascular endothelial growth factor) expression
  • c-kit/SCFR (stem cell factor receptor) coexpression (in 70% of cases): tumor cells of small cell lung cancer express and secrete the stem cell factor which binds to c-kit.^[2]

• There are 4 tumor suppressor genes that are affected with chromosome 3p deletion. These tumor suppressor genes play a role in the development of small cell lung cancer. The genes are:
  • Fragile histidine triad gene (FHIT): the FHIT gene encodes an enzyme called diadenosine triphosphate hydrolase and plays a role in the control of the cell cycle control and favors apoptosis.^[3]
  • RASS effector homologue (RASSF1): RASSF1 stabilizes the cell cycle and induces G2–M arrest, preventing cells from rapidly growing.^[4]
  • Retinoic acid receptor beta
  • FUS1

• The association between smoking and lung cancer is well established.
• Studies from the early 1950’s demonstrated an elevated risk of lung cancer with smoking.^[5][6]
• In particular, small cell lung cancer is highly associated with smoking, even more than the other types of lung cancer.^[7]

• There are more than 60 carcinogens in a cigarette,^[8] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.
• These carcinogens cause oxidative stress through the formation of reactive oxygen species and promote point mutations in different genes, especially in TP53 and KRAS.
• These events culminate in the development of neoplastic cells.^[9][10]
• In addition, nicotine appears to depress the immune response to malignant growth in exposed tissues.

• There are several studies on the association between the exposure to radon and lung cancer.^[11][12][13]
• Radon damages the epithelial lining of the lung by either interacting directly with the cellular DNA and causing chromosomal damage and gene mutations, or indirectly through the effect of free radicals.
• Radon gas emits alpha particles that react with the water molecules, creating several reactive oxygen species that react with other molecules and cause biologic damage to the lung cells.^[14][15][16]

• Small cell lung cancer is one of the most common tumors associated with a paraneoplastic syndrome.
• The most common endocrine condition associated with small cell lung cancer is syndrome of inappropriate antidiuretic hormone (SIADH), where there is an excessive secretion of antidiuretic hormone (ADH) leading to hyponatremia.
• Other conditions that are related to small cell lung cancer are:
  • Production of atrial natriuretic peptide (ANP) leading to hyponatremia, natriuresis and hypotension
  • Ectopic ACTH production, which causes Cushing syndrome
  • Lambert-Eaton syndrome due to the production of antibodies directed against the antigens of the neuromuscular junctions

Small cell lung cancer exhibits the following findings on gross examination:^[17]

• Necrosis
• Central location
• Follows the bronchi

• In small cell lung cancer, the tumor cells are small and round, but they can sometimes be ovoid or spindle shaped.
• The cells have scant cytoplasm with a high mitotic count and hyperchromatic nuclei.
• Nearly all small cell lung cancers are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen.
• Neuroendocrine and neural differentiation result in the expression of molecules like dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1.
• One or more markers of neuroendocrine differentiation can be found in approximately 75% of small cell lung cancers.^[20]

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