pulmonary large cell carcinoma

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PO

Digital cases

 JRC:6238 : Pulmonary undifferentiated large cell carcinoma.
 JRC:6240 : Pulmonary undifferentiated large cell carcinoma.
 JRC:6241 : Pulmonary undifferentiated large cell carcinoma. (Sim. FXS)
 JRC:19396 : Pulmonary undifferentiated large cell carcinoma.
 JRC:19398 : Pulmonary undifferentiated large cell carcinoma.

Definition: Pulmonary large cell carcinoma is composed of large polygonal cells with no evidence of glandular or squamous differentiation. LCCs of the lung are recognized as a diagnostic entity by the current World Health Organization classification of lung neoplasms. However, data suggest that LCCs represent a heterogeneous group of neoplasms.

Large cell carcinoma (LCC) of the lung is 1 of 4 major histopathologic tumor subtypes recognized by current classifications of lung tumors. However, although squamous cell carcinoma (SQCC), adenocarcinoma (ADC), and small cell carcinoma are well-defined entities with typical morphologic, immunophenotypic, and molecular features, LCCs, with the exception of the rare neuroendocrine, rhabdoid, basaloid, and lymphoepithelioma-like subtypes, are defined as "poorly differentiated non–small cell tumors lacking features of ADC and SQCC".

Therefore, the term LCC has frequently and improperly been used as a synonym of "undifferentiated" non–small cell lung carcinoma ( undifferentiated NSCLC) and has been used as a “wastebasket” for tumors lacking a definite morphologic pattern.

Some studies support the hypothesis that most LCCs represent poorly differentiated ADC or SQCC. (ref)

Synopsis

 Tumor with solid nests of large polygonal and anaplastic cells without obvious squamous or glandular differentiation; may be undifferentiated squamous cell carcinoma or adenocarcinoma
 Diagnosis of exclusion - cannot diagnose on small biopsies or in lymph node metastases
 Extended panel of immunohistochemical markers can reclassify 60%; miRNA-based analysis can reclassify the balance, but clinical relevance is unknown (Am J Clin Pathol 2011;136:773)
 80% men
 Often associated with peripheral eosinophilia and leukocytosis, due to tumor production of colony stimulating factor
 Behavior is similar to adenocarcinoma

Macroscopy

 Usually peripheral lung;
 spherical tumor with well-defined borders and bulging, fleshy, homogenous gray-white cut surface
 No anthracosis
 Frequently involves thoracic wall

Microscopy

 Large polygonal cells and anaplastic cells growing in solid nests without obvious squamous or glandular differentiation
 Moderately abundant cytoplasm,
 well defined cell borders,
 vesicular nuclei,
 prominent nucleoli

Variants according to the WHO classification system

 basaloid carcinoma,
 large cell neuroendocrine carcinoma,
 large cell carcinoma with rhabdoid phenotype,
 lymphoepithelial carcinoma

Immunoprofiling

TTF1	CK7	p63	CK5/6
+	+	-	-
-	-	+	+

Notes

Large-cell lung carcinoma (LCLC) is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung.

Classic large cell carcinoma of the lung by definition is a poorly differentiated carcinoma without the presence of any defining features such as keratinization or intercellular bridges seen in squamous cell carcinomas, any gland or mucin formation that would classify the tumor as an adenocarcinoma or small cells with scant cytoplasm and salt-and-pepper-type chromatin characteristic of small cell carcinoma.

Classic large cell carcinoma is a tumor arranged in cellular aggregates or sheets of uniform large cells with indistinct cell borders. The nuclei are round to irregular with vesicular chromatin and prominent nucleoli. Moderate amounts of basophilic cytoplasm are typically seen.

Epidemiology

In most series, LCLC’s comprise between 5% and 10% of all lung cancers.

According to the Nurses’ Health Study, the risk of large cell lung carcinoma increases with a previous history of tobacco smoking, with a previous smoking duration of 30 to 40 years giving a relative risk of approximately 2.3 compared to never-smokers, and a duration of more than 40 years giving a relative risk of approximately 3.6.

Variants

The newest revisions of the World Health Organization Histological Typing of Lung Cancer schema include several variants of LCLC, including:

 (a) basaloid

 (b) clear cell

 (c) lymphoepithelioma-like

 (d) rhabdoid phenotype

 (e) large-cell neuroendocrine carcinoma.

• In addition, a "subvariant", called "combined large-cell neuroendocrine carcinoma", or c-LCNEC, is recognized under the new system.
• To be designated a c-LCNEC, the tumor must contain at least 10% LCNEC cells, in combination with at least 10% of other forms of NSCLC.

 Large cell neuroendocrine carcinoma

• For a diagnosis of large cell neuroendocrine carcinoma, certain criteria have to be met.
• Firstly, the tumors need to show the typical growth pattern of neuroendocrine carcinomas, ie, tumor cells forming organoid nests, rosettes or trabecular structures, and peripheral palisading of tumor cells.
• Tumor cells are large with vesicular nuclei, prominent nucleoli, and abundant cytoplasm.
• Per definition, more than 10 mitoses must be present in 10 high-power fields (HPF), and necrosis is commonly seen.
• In addition to these morphological features, the tumors must show neuroendocrine differentiation either based on the presence of neurosecretory granules as identified by electron microscopy or positive staining for at least one neuroendocrine immunohistochemical stain.

 Combined large cell neuroendocrine carcinoma

• Rarely, large cell neuroendocrine carcinomas can contain components of other non-small cell carcinomas and are then classified as "combined large cell neuroendocrine carcinoma".

 Basaloid carcinoma

• Basaloid carcinoma of the lung is listed as another variant of pulmonary large cell carcinoma.
• These tumors are characterized by a solid nodular growth or formation of anastomosing trabecular structures. A hallmark of this tumor is its prominent peripheral palisading.
• Contrary to large cell neuroendocrine carcinomas, the tumor cells are small and uniform and contain hyperchromatic nuclei with indistinct nucleoli.
• Although cytoplasm is scant, nuclear molding as typically seen in small cell carcinomas is absent.
• Comedo-type necrosis is common and rosette-like structures may be occasionally seen.
• Squamous differentiation should be absent, otherwise the tumor would have to be classified as the basaloid variant of squamous cell carcinoma.
• Although focal positivity of tumor cells may be seen with neuroendocrine markers, high molecular-weight cytokeratin is diffusely expressed in these tumors contrary to neuroendocrine carcinomas.

 Lymphoepithelioma-like carcinoma

• Pulmonary lymphoepithelioma-like carcinoma is morphologically similar to its counterpart in the head and neck area.
• Lymphoepithelioma-like carcinoma characterized by sheets of vesicular tumor cells infiltrated by numerous lymphocytes.
• It is characterized by a prominent syncytial growth pattern and typically has pushing borders to the adjacent pulmonary parenchyma.
• The tumor cells are large, have vesicular nuclei and conspicuous eosinophilic nucleoli.
• The most characteristic feature of this tumor is the infiltration by inflammatory cells, predominantly lymphocytes but also plasma cells, histiocytes, neutrophils, or eosinophils.
• Immunohistochemistry or in situ hybridization usually reveals the presence of Ebstein–Barr virus (EBV) antigen or RNA.

 Clear cell carcinoma

• Clear cell carcinoma of the lung is a tumor characterized by sheets of large polygonal tumor cells with round or irregular nuclei and abundant cytoplasm which is either water clear or has a foamy appearance due to the presence of glycogen.
• The tumor cells contain distinct cell borders and small hyperchromatic nuclei.
• Mitotic figures are infrequent.
• By definition, glandular structures, mucin production, intercellular bridges, and keratinization are absent.

 Large cell carcinoma with rhabdoid phenotype

• Large cell carcinoma with rhabdoid phenotype is a rare tumor of the lung which is defined as a carcinoma that must contain at least 10% of rhabdoid tumor cells.
• These rhabdoid cells contain prominent eosinophilic cytoplasmic globules displacing the nucleus to the periphery.
• These tumors may contain small foci of adenocarcinoma, squamous cell carcinoma, classic large cell carcinoma, or pleomorphic carcinoma and can express neuroendocrine markers by immunohistochemistry.

Molecular biology

 Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria. 2016. http://dx.doi.org/10.5858/arpa.2015-0361-OA

See also

 pulmonary carcinomas (lung cancer )
 large cell carcinomas

Open references

  Molecular biology

 Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria. 2016. http://dx.doi.org/10.5858/arpa.2015-0361-OA

 Heterogeneity of Large Cell Carcinoma of the Lung. Barbareschi M et al. AJCP 2011. http://ajcp.ascpjournals.org/content/136/5/773.full