Lung cancer

Lung cancer is the leading cause of cancer-related death worldwide. Smoking is accepted as the major risk factor, responsible for 70-90% of all cancer cases, although the etiology of lung cancer appears multifactorial with both environmental and genetic factors playing a role. One important reason for the poor outcome of patients with lung cancer is that the disease is commonly diagnosed in advanced stages and therefore often not resectable by surgery. Symptoms of lung cancer are unspecific and dependent on anatomical site and include persistent coughing, hemoptysis, repeated pneumonia and signs of respiratory distress.

Lung cancer can principally be divided into non-small cell carcinoma and small cell carcinoma:

• Non-small cell carcinoma is suggested to originate from bronchogenic or alveolar cells and represents the most common form of primary lung cancer. Patient therapy is based on the tumor extent. In principle, limited stage tumors are treated surgically, sometimes with the addition of chemotherapy and radiotherapy. The treatment of advanced stages depends on the molecular background of the tumor and individual patient parameters. If the tumor harbors a targetable genomic aberration, like mutations of the genes EGFR or MET, or gene fusions involving ALK or ROS1, specific small inhibitors are chosen. If targeted treatment is not possible, the newly developed checkpoint inhibitors (immunotherapy) are recommended either alone or in combination with chemotherapy.

• Small cell lung carcinoma originates from neuroendocrine cells and accounts for approximately 15% of all primary lung cancers. This extremely rapidly proliferating cancer is generally treated with chemotherapy, sometimes in combination with radiotherapy, leading initially to good tumor response. However, after initial response, small cell lung carcinoma nearly always progresses, with only anecdotal long term survivors.

The histology-based classification has gained a significant clinical impact, as molecular testing as well as chemotherapy are guided by the histological subtype.

Non-small cell carcinomas are classified as adenocarcinoma or squamous cell carcinoma based on morphology and the expression of markers of differentiation. In the absent of specific histology and marker expression, the tumor may be classified as large cell carcinoma. Other rare entities include large cell neuroendocrine carcinomas, pleomorphic carcinoma and mixed tumors. Necrosis, hemorrhage and abundant mitotic figures are common features in non-small cell lung carcinomas. As in several other forms of cancer, the infiltration of various inflammatory cells can be prominent and is linked to patient prognosis.

• Adenocarcinomas can be further classified based on the dominant growth pattern, as papillary, acinic, solid, micropapillary and lepidic subsets. This classification is considered to imply prognostic information, but is of minor clinical relevance. Some adenocarcinomas show extensive mucin production and are termed mucinous or colloid carcinomas. The typical adenocarcinomas of the lung show differences in degree of pleomorphism, cellular atypia, rate of mitotic figures and formation of glandular structures.

• Squamous cell carcinoma is suggested to originate from metaplastic squamous epithelia in the bronchial tree. It is defined by a variable degree of squamous differentiation, such as keratinization or intercellular bridging. The degree of squamous differentiation provides the basis for determining if the carcinoma is well, moderately or poorly differentiated.

Small cell carcinoma represents the end of the spectrum of poorly differentiated neuroendocrine tumors and is a highly aggressive tumor with an extremely poor clinical outcome independent of stage. Signs of neuroendocrine differentiation can be difficult to visualize and the diagnosis is mainly based on morphological appearance. These tumors are characterized by the proliferation of primitive-appearing relatively small tumor cells of about double or triple the size of an ordinary lymphocyte. The tumor grows in randomly arranged sheets of a homogeneous population of tumor cells separated by thin fibrous septa. Necrosis is extensive and a common feature of these tumors.

Diagnostics of lung cancer subtypes is principally based on morphology, although immunohistochemistry markers are important in the absence of clear features of differentiation. In adenocarcinoma the expression of TTF1 or napsin A is common, whereas squamous cell carcinomas are positive for cytokeratin 5 and 6, p63 as well as p40. Immunohistochemistry also plays an important role to distinguish primary lung carcinomas from lung metastases from other organs.