Histopathological Transformation to Small-Cell Lung Carcinoma in Non-Small Cell Lung Carcinoma Tumors

Rita Dorantes-Heredia; José Manuel Ruiz-Morales; Fernando Cano-García

Disclosures

Transl Lung Cancer Res. 2016;5(4):401-412. 

In This Article

Abstract and Introduction

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.

Introduction

Lung cancer represents the primary cause of cancer mortality worldwide.[1] The World Health Organization (WHO) classifies lung cancer into two subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).[2] NSCLC represents 85% of cases of lung cancer, and is divided into adenocarcinoma, squamous-cell, and large-cell carcinoma.[3] SCLC represents 14–15% of all lung cancers, and more than 30,000 new cases are diagnosed each year in the United States.[4]The oncogenes involved in lung cancer development have been studied extensively and a great variety of tumor promoter and suppressor genes play important roles in the development of lung cancer.[5]

Promoter gene alterations: in NSCLC it is common to observe mutations in KRAS,[6]HRAS,[7] and NRAS (11p15.5; 1p13).[8] Specifically, lung adenocarcinoma can harbor overexpression of the epidermal growth factor receptor (EGFR),[9]ROS proto-oncogene 1,[10] and rearrangements of the anaplastic lymphoma kinase (ALK).[11] All of these alter autocrine and paracrine cell growth.[12] Adenocarcinoma and neuroendocrine large-cell carcinoma, can have amplification and overexpression of c-myc,[13]l-myc,[14] and n-myc (1p32; 2p2.41).[15] These augment proliferation and inhibit cell differentiation.[16] Suppressor gene alterations: neuroendocrine carcinoma and NSCLC can have missense mutation in p53 (17p12–13), which inactivates tumor suppression.[17] In SCLC, mutation and deletion in retinoblastoma 1 (RB1) (13q14) can be observed, which produces loss of control of the G1 phase of the cell cycle and the arrest of the cell cycle.[18]

Alterations in the methylation pattern of DNA have been recognized in many human cancers, and lung cancer is no exception. Aberrant promoter methylation has been shown in various genes, including the retinoid acid receptor β-2, tissue inhibitor of metalloproteinase-3, p16, O6-methylguanine-DNA-methyltransferase, death-associated protein kinase, E-cadherin, p14, glutathione S-transferase P1, the ras effector homologue RASSF1A, and the protein tyrosine phosphatase receptor type O. The presence of aberrant methylation in precursor lesions of lung carcinomas identifies it as a reasonable candidate biomarker for early lung cancer diagnosis.[5]

Advanced clinical stages of NSCLC that harbor mutations in EGFR, ROS-1, or ALK rearrangements have a distinct clinical course compared with conventional NSCLC. The use of modern therapies for lung cancer such as tyrosine kinase inhibitors (TKIs), some of which inhibit EGFR and others ALK, has improved survival in patients with specific genetic anomalies of their tumors.[19–21] These treatments are preferred over standard intravenous chemotherapy, not only because of their advantages in terms of outcomes, but also because of the better quality of life that patients report. Other advantages include fewer visits to chemotherapy infusion centers and the convenience of administration.[22] However, most patients develop resistance to the treatment after 12–15 months of continuous therapy.[23–26] This review is focused on standards not only for analysis of the histopathological structure, but also in the molecular mechanisms that drive the histopathological transformation to SCLC in NSCLC tumors.

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