Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Abstract

Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuron-specific enolase.

Keywords: Anaplastic lymphoma kinase (ALK); drug resistance; epidermal growth factor receptor (EGFR); neuroendocrine cells.

Figure 1

Small cell lung carcinoma. Hematoxylin and eosin (H&E) stain. Tumor composed of nests of small cells with fine granular chromatin nuclei, inconspicuous nucleoli, and scarce cytoplasm.

Figure 2

Small cell lung carcinoma. Positive immunohistochemistry (IHC) for CD56, with membranous pattern. This supports the neuroendocrine lineage of the neoplastic cells.

Figure 3

Molecular mechanisms involved in the transformation from NSCLC to SCLC. They include TP53 mutations, RB1 loss, lack of EGFR expression and MYC amplification. The most studied signaling pathway is the ASCL1 which is regulated by four different NOTCH receptors. NOTCH alterations promote ASCL1 and CD56 overexpression. These changes induce CDK5 activity and inactivation of RB by phosphorylation. With inactivated RB, p53 mutated cells have a selective advantage. NSCLC, non-small cell lung carcinoma; SCLC, small cell lung carcinoma; RB1, retinoblastoma 1; EGFR, epidermal growth factor receptor; NOTCH, neurogenic locus notch homolog; ASCL1, achaete-scute homolog 1; CDK5, cyclin-dependent kinase 5.