Lung Cancer Part 1 (Small Cell & Non-Small Cell)


  • Lung cancer is the result of tumors that form in the respiratory epithelium of the bronchi, bronchioles, and alveoli.
  • Lung cancer is a key cause of cancer death worldwide, in both men and women.
  • Although lung cancer is often asymptomatic in the early stages (and, thus, often goes undetected), later stages can be marked by chest pain, cough, dyspnea, and hemoptysis.
  • Complications of lung cancer depend on the location of tumors and the cell type; we’ll address complications in more detail, elsewhere.
  • Often found incidentally on chest x-ray or CT.
  • Once a tumor is found, determination of the type of lung cancer relies on histopathology and molecular analysis.
  • Tobacco cigarettes contain multiple toxins and carcinogens, and smoking is the number one cause of lung cancer, accounting for 80-90% of all lung cancer cases.
  • Other causes include asbestos, radon, polycyclic aromatic hydrocarbons (produced when coal, wood, etc. are burned), and various metals (ex: nickel, chromium).
    – Although the role of electronic cigarettes in lung cancer in humans is uncertain, studies are showing that electronic cigarettes can induce lung cancer in mice.
  • Most genetic mutations associated with lung cancer are non-heritable, and are associated with exposure to carcinogens.
    – Genetic changes are variable, and include driver mutations, amplifications, translocations, deletions, and insertions.
  • Pleural mesothelioma is cancer of the lung pleura; it is most often caused by exposure to asbestos (which comprises long, thin fibers found in some building and construction materials).
    – Pleural thickening and effusions are common in mesothelioma, which is notoriously difficult to treat.


Lung cancer is broadly divided into small-cell lung cancer and non-small cell lung cancer.

Small-cell lung cancer, aka, oat cell carcinoma.

  • Accounts for approximately 15% of lung cancer cases.
  • Often centrally located, with formation of tumors in the airways submucosa and perihilar masses.
  • Aggressive, rapid growth and early dissemination, often to the brain, liver, and bones.
  • Histopathology
    – Small, spindle-shaped cells with a high mitotic rate (due to rapid growth).
    – Cells have scant cytoplasm and contain granular chromatin.
    – Necrosis is common.
    – Cancerous cells arise from neuroendocrine cells (called Kulchitsky cells) in the basal bronchial epithelium.
    – Small-cell cancer may be “pure” or “combined” with large cells and/or non-small lung cancer cells.
  • Small-cell cancer is almost always caused by cigarette smoking.
  • MYC oncogene mutations and RB1 and TP53 inactivations (which facilitate uncontrolled tumor growth).
  • We can tie key biomarkers to the fact that these tumors arise from neuroendocrine cells:
    – The following neuroendocrinal markers are often used to help identify small-cell lung cancer:
    Neuron-specific enolase, Chromagranin A, Synaptophysin, and CD56.
  • Lastly, this type of lung cancer is associated with a variety of complications, including superior vena cava syndrome, SIADH, Cushing Disease, and Lambert-Eaton syndrome.

Non-small cell lung carcinomas (NSCLC)

Collectively account for approximately 85% of all lung cancers.

Be aware that significant WHO reclassifications occurred in 2004 and 2015 due to advances in immune-histological and molecular techniques. We will follow these updated classification schemes, but be aware of significant intertextual variation.


  • Accounts for 40% of all lung cancers.
  • Most commonly (though not always) found in the peripheral lung tissues, affecting airway epithelial type II alveolar cells.
  • Distant metastases are common.
  • 5 histological subtypes of adenocarcinoma
    – More than one type may be present in a tumor
    – Mucinous and non-mucinous forms exist.
    –  Lepidic subtype is characterized by cancer cells that follow the lining of the alveolar walls; note that there is no disruption to the respiratory tissue architecture. Adenocarcinomas with predominantly lepidic patterns have the best prognosis.
    – Acinar patterns are, as their name suggests, comprised of cuboidal and/or columnar shaped cells that form acini and tubules.
    – Papillary pattern comprises columnar cells surrounding a fibroblastic core.
    – Micropapillary pattern is similar to papillary but smaller and lack fibroblastic cores – these small “tufts” of cells may appear to float in the alveolar spaces. Micropapillary adenocarcinoma has a relatively poor prognosis.
    –  Solid pattern comprises dense sheets or “nests” of cells;show that ribbons of fibrosis may weave around the nests. This pattern also has a poor prognosis.
  • Be aware that the subtypes “bronchoalveolar cell carcinoma” and “mixed adenocarcinoma” are no longer in use, and that “clear cell,” “rhabdoid,” and “signet” are now used as descriptive terms, not subtype labels.
  • Invasiveness of adenocarcinoma varies
    – Pre-invasive forms are predominantly lepidic, and include Atypical Adenomatous Hyperplasia (AAH) and Adenocarcinoma in situ (AIS).
    – Minimally invasive carcinomas comprise both lepidic and more invasive cell types that infiltrate the myofibroblastic stroma (but no invasion into the pleura or circulation). These tumors are often non-mucinous.
    – Invasive adenocarcinoma is characterized by a tumor focus greater than 5 mm, and comprises a mixture of histologic patterns. Tumors are classified according to the predominant histologic pattern (for example, invasive adenocarcinoma with predominant papillary pattern). These tumors are often mucinous.
  • Key Points:
    – Adenocarcinoma is most common lung cancer overall.
    – It is the most common lung cancer in women and in non-smokers.
    – Genetic mutations, including EGFR, KRAS, and ALK are associated with adenocarcinoma, and are the focus of key targeted therapies.

Squamous cell carcinoma

  • Accounts for approximately 30% of lung cancers.
  • Most often arises centrally in the bronchial tubes; however, write that peripheral tumors are associated with cavitation.
  • 3 Histopathological Subtypes: basaloid, non-keratinized, and keratinized.
    – Some former subtypes have been discontinued, and those subtype names are now used as descriptive terms (ex: clear cell).
  • Histopathology
    – *Nests of polygonal cells with eosinophilic cytoplasm and obvious nucleoli
    – Under high magnification, we can see intercellular bridges.
    – Keratin pearls are another common features; these are accumulations of keratin between the nests of polygonal cells.
    – Necrosis may also be present.
  • Key Points:
    – Squamous cell carcinoma is strongly associated with cigarette smoking, and with TP53 and P-450 mutations.
    – A notable complication is hypercalcemia due to parathyroid hormone-related protein (PTH-rp) production; common symptoms of this include weakness, nausea, vomiting, abdominal cramps, and dehydration.

Large cell carcinoma

  • Accounts for approximately 10% of lung cancers.
  • Often peripherally located.
  • Histopathology: tumors comprise poorly differentiated, large cells.
  • Strongly associated with cigarette smoking.
  • It’s important to know that several “subtypes” have been reclassified/reorganized; for example, this group no longer includes Large Cell Neuroendocrine Carcinoma, which is now grouped with small cell neuroendocrine tumors.
  • Large cell lung cancer is a diagnosis of exclusion, and diagnosis relies on surgical resection.
  • When relying on cytology alone, the term “non-small cell lung carcinoma, not otherwise specified” (NSCLC-NOS) is preferred.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s