Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy

Abstract

Recent large scale genomic studies from the Clinical Lung Cancer Genome Project have identified different driver gene mutations in the subtypes of non-small cell lung carcinoma (NSCLC). These findings not only lead to remarkable progress in targeted therapies for lung cancer patients, but also provide fundamental knowledge for the subclassification of NSCLC. More recently, the advancement and clinical application of immunotherapy have reinforced the need for the accurate subclassification of NSCLC. In 2015, the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) updated their guidelines for the subclassification of lung cancers. These guidelines emphasize: (1) the subclassification of NSCLC, (2) the critical role of molecular characterization of tumors for targeted therapy, (3) the unique terminology for subclassifying NSCLC using small biopsy specimens, and (4) the utility of IHC biomarkers in the accurate diagnosis and subclassification of lung cancer. The guidelines have significant prognostic impact on oncologic practice and patient care. In this review, we summarize the current WHO guidelines for the classification of lung cancer, discuss advancements of targeted therapy and immunotherapy, and address the utility and limitation of immunomarkers in the subclassification of NSCLC, as well as the prospective future of the field.

Keywords: EGFR mutations; Fine needle aspiration (FNA) biopsy; Non-small cell lung carcinoma (NSCLC); PD-L1 immunotherapy; Targeted therapy.

Figure 1

Collection of Tumor tissue by FNA (fine needle aspiration) biopsies, and histomorphology of normal lung parenchyma, ADC and SqCC. Tumor tissue may be collected by endoscopic techniques, such as transbronchial FNA with or without ultrasound guidance, or transthoracic techniques with CT or ultrasound guidance.

Figure 2

Subclassification of small biopsy specimens. The diagnosis of ADC and SqCC can be made by finding evidence of glandular differentiation and cytokeration formation, respectively. However, the subclassification of a poorly differentiated carcinoma without obvious glandular or cytokeratin formation may require the use of a panel of IHC markers. The molecular characteristics of the tumor play a critical role for targeted therapy.

Figure 3

Normal basal layer of bronchial cells is immunoreactive with P40 and P63. They should not be confused with squamous cell carcinoma. A, H&E stain of normal bronchial cells; B, immunostain of P40; and C, immunostain of P63.

Figure 4

The utility of a triple marker. We have combined three individual markers (TTF-1,Napsin A and P40) into a single marker to subclassify NSCLC.

Figure 5

The work flow for the differential diagnosis of NSCLC using the triple marker. Based on the histomorphological assessment of the specimen, different immunomarkers are performed.