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:
- 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.
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.
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. 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).
- MAPK kinase 1 (MAP2K1 or MEK1).
- MET, which encodes the hepatocyte growth factor receptor (HGFR).