In English | En español
Questions About Cancer? 1-800-4-CANCER

Non-Small Cell Lung Cancer Treatment (PDQ®)

  • Last Modified: 02/21/2014

Page Options

  • Print This Page
  • Print This Document
  • View Entire Document
  • Email This Document

Cellular Classification of NSCLC

WHO/IASLC Histologic Classification of NSCLC
        Squamous cell carcinoma
        Large cell carcinoma
        Neuroendocrine tumors
        Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
        Molecular Features

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

  • Squamous cell carcinoma (25% of lung cancers).
  • Adenocarcinoma (40% of lung cancers).
  • Large cell carcinoma (10% of lung cancers).

There are numerous additional subtypes of decreasing frequency.[1]

WHO/IASLC Histologic Classification of NSCLC
  1. Squamous cell carcinoma.
    1. Papillary.
    2. Clear cell.
    3. Small cell.
    4. Basaloid.

  2. Adenocarcinoma.
    1. Acinar.
    2. Papillary.
    3. Bronchioloalveolar carcinoma.
      1. Nonmucinous.
      2. Mucinous.
      3. Mixed mucinous and nonmucinous or indeterminate cell type.
    4. Solid adenocarcinoma with mucin.
    5. Adenocarcinoma with mixed subtypes.
    6. Variants.
      1. Well-differentiated fetal adenocarcinoma.
      2. Mucinous (colloid) adenocarcinoma.
      3. Mucinous cystadenocarcinoma.
      4. Signet ring adenocarcinoma.
      5. Clear cell adenocarcinoma.

  3. Large cell carcinoma.
    1. Variants.
      1. Large cell neuroendocrine carcinoma (LCNEC).
      2. Combined LCNEC.
      3. Basaloid carcinoma.
      4. Lymphoepithelioma-like carcinoma.
      5. Clear cell carcinoma.
      6. Large cell carcinoma with rhabdoid phenotype.

  4. Adenosquamous carcinoma.

  5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
    1. Carcinomas with spindle and/or giant cells.
    2. Spindle cell carcinoma.
    3. Giant cell carcinoma.
    4. Carcinosarcoma.
    5. Pulmonary blastoma.

  6. Carcinoid tumor.
    1. Typical carcinoid.
    2. Atypical carcinoid.

  7. Carcinomas of salivary gland type.
    1. Mucoepidermoid carcinoma.
    2. Adenoid cystic carcinoma.
    3. Others.

  8. Unclassified carcinoma.

Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.


Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histologic subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

  • Well-differentiated fetal adenocarcinoma.
  • Mucinous (colloid) adenocarcinoma.
  • Mucinous cystadenocarcinoma.
  • Signet ring adenocarcinoma.
  • Clear cell adenocarcinoma.
Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including the following:

  • LCNEC.
  • Basaloid carcinoma.
  • Lymphoepithelioma-like carcinoma.
  • Clear cell carcinoma.
  • Large cell carcinoma with rhabdoid phenotype.

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Neuroendocrine tumors

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[2] In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. Other mutations of potential relevance to treatment decisions include:

  • Kirsten rat sarcoma viral oncogene (KRAS).
  • Anaplastic lymphoma kinase receptor (ALK).
  • Human epidermal growth factor receptor 2 (HER2).
  • V-raf murine sarcoma viral oncogene homolog B1 (BRAF).
  • PIK3 catalytic protein alpha (PI3KCA).
  • AKT1.
  • MAPK kinase 1 (MAP2K1 or MEK1).
  • MET, which encodes the hepatocyte growth factor receptor (HGFR).

These mutations are mutually exclusive, except for those in PIK3CA and EGFR mutations and ALK translocations.[3]

EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13–17), 6% from current smokers (20 of 344; 95% CI, 4–9), and 52% from never-smokers (302 of 580; 95% CI, 48–56; P < .001 for ever- vs. never-smokers).[4]

Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Other mutations that occur in less than 5% of NSCLC tumors include:

  • HER2, present in 2% of tumors.
  • PI3KCA, present in 2% of tumors.
  • AKT1, present in 1% of tumors.
  • BRAF mutations, present in 1% to 3% of tumors.

BRAF mutations are mutually exclusive of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also known as MEK) have been identified in 1% of NSCLC. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

  1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. 

  2. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011.  [PUBMED Abstract]

  3. Tiseo M, Gelsomino F, Boggiani D, et al.: EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 71 (2): 241-3, 2011.  [PUBMED Abstract]

  4. D'Angelo SP, Pietanza MC, Johnson ML, et al.: Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol 29 (15): 2066-70, 2011.  [PUBMED Abstract]