Large cell carcinoma of the lung pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Overview
Large cell carcinoma of the lung arises from the epithelial cells of the lung, which are usually involved in the lining of the airways. The pathological irritation causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells to be replaced by stratified squamous epithelium. Large cell carcinoma of the lung has a peripheral location, and usually appears as a well-circumcised mass attached to the thoracic wall. Large cell carcinoma of the lung is a rapidly growing cancer. The histologic subtype of large cell neuroendocrine tumor is related with a more aggressive presentation. Genes involved in the pathogenesis of large cell carcinoma of the lung, include: EGFR, LKB1, KRAS, HER2, and ALK. On gross pathology, large cell carcinoma of the lung is characterized by well-defined borders, spherical morphology, homogeneous gray-white surface, and bulging appearance. On micropathology, large cell carcinoma of the lung is characterized by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin. On immunohistochemistry characteristic features of large cell carcinoma of the lung, include: loss of staining with CK5/6, and positive immunoreactivity to EGFR, PDGFR-alpha, and c-kit.
Pathogenesis
- Large cell carcinoma of the lung arises from the epithelial cells of the lung, which are usually involved in the lining of the airways.
- The pathological irritation causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells to be replaced by stratified squamous epithelium.[1]
- Large cell carcinoma of the lung has a peripheral location, and usually appears as a well-circumcised mass attached to the thoracic wall.
- Large cell carcinoma of the lung is a rapidly growing cancer.
- The histologic subtype of large cell neuroendocrine tumor is related with a more aggressive presentation.[1]
Precursor lesions
- There are no precursor lesions associated with most of the types of large cell carcinoma except for basaloid carcinoma.
| Variants of LCC | Precursor lesions |
|---|---|
| Adjacent squamous dysplasia | Bronchial preneoplastic lesions |
| Lymphoepithelioma-like carcinoma | EBV viral infection (viral [EBER1] dependent transformation) |
Histogenesis
- Large cell carcinomas (LCC) commonly originate from a pluripotent progenitor cells.
- The tumor subtypes of LCC generally follows a proximal‐to‐distal distribution pattern moving distally from the trachea.
- Lung tumors initiated by oncogenic K‐Ras activation appeared to be derived from cells located in the bronchioalveolar duct junction (BADJ).
Role of BASCs in large cell carcinoma
- Bronchioalveolar duct junction (BADJ) contains cells that expresses both Clara‐specific and alveolar‐specific markers.
- These cells are bronchioalveolar stem cells (BASCs).
- Activation of KRAS results in differentiation of BASC's leading to adenoma formation.
| BASC Dual positive cells | |||||||||||||||||||||||||||||||||||||||||||
| K‐Ras activation | |||||||||||||||||||||||||||||||||||||||||||
| Adenoma formation | |||||||||||||||||||||||||||||||||||||||||||
| Tumor markers for Lung carcinoma |
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Two hypotheses explaining the origin of NE variants of large cell carcinoma
- Neuroendocrine bodies (NEBs) are cellular bodies in the epithelial lining of the bronchi.
- Neuroendocrine bodies (NEBs) harbor pulmonary neuroendocrine cells (PNECs).
- PNECs are associated with variant clara expressing cells (vCEs).
- Mutation or loss of Rb1 gene function along with Trp53 results in neuroendocrine tumors arising from hyperplasia of PNEC.
| Pulmonary neuroendocrine cells(variant Clara expressing cells) | |||||||||||||||||||||||||||||||||||||||||
| Loss of Rb1 + Trp53 function | |||||||||||||||||||||||||||||||||||||||||
| Neuroendocrine hyperplasia | |||||||||||||||||||||||||||||||||||||||||
Genetics
- Development of large cell carcinoma of the lung is the result of multiple genetic mutations[1]
- Genetic mutations play an important role in the treatment selection for large cell carcinoma of the lung
- Genes involved in the pathogenesis of large cell carcinoma of the lung include:[2]
Associated Conditions
Common conditions associated with large cell carcinoma of the lung include:[3]
- Paraneoplasic syndromes such as:
- Humoral hypercalcemia of malignancy.
- Syndrome of inappropriate antidiuretic hormone production
- Cushing’s syndrome
- Carcinoid syndrome
Gross Pathology
- On gross pathology, characteristic findings of tumors associated with large cell carcinoma of the lung, include:[4]
- Well-defined borders
- Spherical morphology
- Homogeneous gray-white surface
- Sectioning reveals a soft, pink-tan tumor with frequent necrosis, occasional hemorrhage and rarely, cavitation.
- Bulging appearance
- Basaloid carcinomas characteristically show exophytic bronchial growth
- Size greater than 4cm
- Peripheral masses (large cell neuroendocrine carcinomas)
- Tumor often invades visceral pleura, chest wall, or adjacent structures.
Microscopic Pathology
- On microscopic pathology, characteristic findings of tumors associated with large cell carcinoma of the lung include:[4]
- Larger size of the anaplastic cells.
- A higher cytoplasmic-to-nuclear size ratio.
- Lack of "salt-and-pepper" chromatin.
| Variant of LCC | Microscopic pathology |
|---|---|
| Large cell neuroendocrine carcinoma (LCNEC) |
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| Basaloid carcinoma |
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| Lymphoepithelioma-like carcinoma |
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| Clear cell carcinoma |
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| Large cell carcinoma with rhabdoid phenotype |
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| Mixed |
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Immunohistochemistry
On inmunohistochemistry, findings associated with large cell carcinoma of the lung, include:[4]
- Loss of staining with CK5/6
- Positive immunoreactivity to EGFR, PDGFR-alpha, and c-kit
Large cell neuroendocrine carcinoma (LCNEC) :
Positive for atleast one of the following:
- Chromogranin
- Synaptophysin
- NCAM (CD56)
Around 50% of LCNEC express TTF-1 but expression of CK 1, 5, 10, 14, 20 (34ßE12) is uncommon.
Basaloid carcinoma:
- Immunohistochemical stains for neuroendocrine markers are geneally negative.
- Cytokeratin expression is as seen in NSCLC
- Includes CK 1, 5, 10, and 14 (34ßE12) markers
- Basaloid carcinoma does not express TTF-1
Lymphoepithelioma-like carcinoma
- EBER-1 RNA +
References
- ↑ 1.0 1.1 1.2 Davidson MR, Gazdar AF, Clarke BE (2013). "The pivotal role of pathology in the management of lung cancer". J Thorac Dis. 5 Suppl 5: S463–78. doi:10.3978/j.issn.2072-1439.2013.08.43. PMC 3804871. PMID 24163740.
- ↑ Shi WY, Liu KD, Xu SG, Zhang JT, Yu LL, Xu KQ, Zhang TF (2014). "Gene expression analysis of lung cancer". Eur Rev Med Pharmacol Sci. 18 (2): 217–28. PMID 24488911.
- ↑ Kanaji N, Watanabe N, Kita N, Bandoh S, Tadokoro A, Ishii T, Dobashi H, Matsunaga T (2014). "Paraneoplastic syndromes associated with lung cancer". World J Clin Oncol. 5 (3): 197–223. doi:10.5306/wjco.v5.i3.197. PMC 4127595. PMID 25114839.
- ↑ 4.0 4.1 4.2 Miller YE (2005). "Pathogenesis of lung cancer: 100 year report". Am. J. Respir. Cell Mol. Biol. 33 (3): 216–23. doi:10.1165/rcmb.2005-0158OE. PMC 2715312. PMID 16107574.