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.
• 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.

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
CD133 (prominin-1) CD44 (membrane-bound glycoprotein) CD133+ESA+ CD90 CD87 (uPAR) CD166+ CD44+ and CD166+EpCAM+

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
• 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:

• EGFR
• ALK
• KRAS
• HER2

Associated Conditions

Common conditions associated with large cell carcinoma of the lung include:

• 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:

• 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:

• 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)	Organoid nesting Trabecular growth Rosettes and peri-lobular palisading patterns The tumors cells are generally large, with moderate to abundant cytoplasm Nucleoli are frequent, prominent and their presence facilitates separation from small cell carcinoma Mitotic counts are typically 11 or more (average 75) per 2 mm2 of viable tumors Large zones of necrosis are common
Basaloid carcinoma	Solid nodular or anastomotic trabecular cells Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform Moderately hyperchromatic nuclei Absent or focal nucleoli Scant cytoplasm with no nuclear molding High mitotic rate Squamous differentiation is absent Hyalin or mucoid degeneration in the stroma Comedo type necrosis Rosettes
Lymphoepithelioma-like carcinoma	Syncytial growth pattern Large vesicular nuclei Prominent eosinophilic nucleoli Heavy lymphocytic infiltration Lymphocytes admixed with Plasma cells Histiocytes Occasional neutrophils or eosinophils Infiltrating in the form of diffuse sheets Intratumorsal amyloid deposition
Clear cell carcinoma	Large polygonal tumors cells with water-clear or foamy cytoplasm Tumor cells may or may not contain glycogen
Large cell carcinoma with rhabdoid phenotype	Eosinophilic cytoplasmic globules consisting of intermediate filaments, which may be positive for vimentin and cytokeratin Pure large cell carcinomas with a rhabdoid phenotype are very rare Small foci of adenocarcinoma {1803}, and positive neuroendocrine markers may be seen Ultrastruscturally the eosinophilic inclusions are composed of aggregates of large intra cytoplasmic paranuclear intermediate filaments Cells with rhabdoid features may be seen focally in other poorly differentiated NSCLC
Mixed	Large cell neuroendocrine carcinoma with components of Adenocarcinoma Squamous cell carcinoma Giant cell carcinoma Spindle cell carcinoma Histologically heterogeneous

Immunohistochemistry

On inmunohistochemistry, findings associated with large cell carcinoma of the lung, include:

• 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

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