10 Chapter 1 Introduction Lung cancer is the leading cancer type among men worldwide and, after prostate and skin cancer, the most common malignancy in the Netherlands. In recent decades, there has been an increase in the incidence of lung cancer among women. Each year, over 14,000 men and women in the Netherlands are diagnosed with lung cancer, that includes non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Annually, about 10,000 patients die from their disease1. The 5-year survival rate is relatively low at 17%, although small improvements have been observed recently2. Pathology plays a crucial role in the diagnosis, staging, and treatment of NSCLC, which is the most common type of lung cancer (70%). For an adequate diagnosis, pathologists use, beside cytology specimen, tissue samples obtained through biopsy or surgical resection to generate a diagnosis of lung cancer. The morphologic examination includes examination of cells and the structural relation of these cells. To this end, the initial diagnostic step is the conventional hematoxylin and eosin (H&E) staining and is often employed along with supplemental histochemical and/or immunohistochemical stainings. This pathological analysis is critical in determining the type of lung cancer and in differentiation from metastases to the lung, derived from other organs. At the time of diagnosis of NSCLC, the extent of the disease, i.e., the stage is determined. Pathological examination can be supportive in determining the size of the tumor, and depending on where the sample is taken from, it can also help in assessing the presence of metastases, either locoregional in lymph nodes or at distant places for instance in other organs. Pulmonologists and oncologists need this information in determining the stage of the disease and treatment plan. Classification and staging The most prevalent type of lung cancer is NSCLC, which constitutes 70% of all pathologically diagnosed cases. Treatment for lower stage NSCLC involves a combination of surgery and other therapies. SCLC accounts for 11% of cases and is typically already metastasized at the time of diagnosis, ruling out surgical intervention. Carcinoids are rare, comprising only 1% of cases. The remaining 17% of clinically diagnosed cases are suspected to be early-stage NSCLC and are referred for treatment by stereotactic radiotherapy without a pathologic diagnosis2. The recognition of the diversity of NSCLC has led to further subclassification, which was published in the 2004 and 2015 World Health Organization (WHO) classification3, 4. The major types of NSCLC include adenocarcinoma (AdC), squamous cell carcinoma (SqCC), and large cell carcinoma (LCC). Adenocarcinomas can be further subdivided into the most common non-mucinous variant and the mucinous variant. The WHO classification of non-mucinous lung adenocarcinoma in 2015 states that the predominant pattern observed determines the subtype of the tumor4. This assessment
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