Small cell lung cancer (SCLC) accounts for approximately 15% of cases. It is typically central in location. Growth is rapid, with 50% to 75% of patients manifesting evidence of metastatic disease beyond the chest at the time of clinical presentation and initial staging. These tumors derive from endocrine cells of the bronchial mucosa and can produce a variety of paraneoplastic syndromes (see Chapter 92). Untreated, the course of illness is rapid, with a median survival of only a few months. However, these tumors tend to be very responsive to chemotherapy (see below).

One quarter to one third of patients with NSCLC present with localized disease (stages I and II). Another quarter to third have locally or regionally advanced disease (stages IIIA and IIIB), and a third to a half present with advanced disease and distant metastases (stage IV). Survival is a function of stage at the time of presentation, with nearly 40% of those with localized disease surviving 5 years, 20% to 25% of those with stage IIIA, 7% to 10% of those with stage IIIB, and approximately 2% of patients with metastatic disease surviving 5 years (Table 53-1). Overall survival for all patients is approximately 16%. Within this category are adenocarcinomas, squamous cell (epidermoid) carcinomas, and large cell carcinomas.

Adenocarcinomas have become the most common lung cancers, accounting for approximately 40%, and make up a higher percentage of the carcinomas in women. Many of these present peripherally. They sometimes arise in areas of fibrosis secondary to prior pulmonary parenchymal damage. Cancers of this cell type are less closely associated with smoking than others. Distinct subsets of patients have cancers with mutations in oncogenic proteins and respond well to inhibitors of these mutant proteins.

Squamous cell (epidermoid) carcinoma is the second most common lung cancer, accounting for approximately 30%. It is strongly associated with smoking. These tumors commonly occur centrally and can produce bronchial obstruction. They tend to ulcerate and may cause bleeding.

Large cell carcinomas account for approximately 10% to 15% of all lung cancers, and the incidence appears to be decreasing. These cancers tend to metastasize hematogenously relatively early, leading to disease in the bones, liver, and brain.

Clinical presentation is partially a function of tumor location; central endobronchial lesions may produce symptoms early in the course of illness. Hemoptysis, cough, sputum production, and a localized wheeze are among symptoms reported in early phases; however, the frequency with which these symptoms are noted in early stages of disease is low. Hemoptysis occurs as a presenting symptom in only 7% to 10% of patients with lung cancer, although up to 40% will report hemoptysis at some time in their illness. Rarely, a systemic syndrome, such as hypertrophic osteoarthropathy (see Chapter 45), peripheral neuropathy, or inappropriate secretion of antidiuretic hormone, may precede other evidence of disease (see Chapter 92).

Symptoms of advanced disease include anorexia, weight loss, nausea and vomiting, hoarseness (recurrent laryngeal nerve involvement), pleuritic chest pain, bone pain, and neurologic deficits. In patients who present with metastasis or in whom metastasis later develops, the most frequently involved sites include local or regional lymph nodes within the chest (25% to 45%), liver (30% to 45%), bone and bone marrow (20% to 40%), and central nervous system (20% to 35%).

Overall 5-year survival remains at approximately 16%. The poor prognosis is related in large part to the advanced stage of disease at the time of diagnosis. Unfortunately, local and regional disease is most often asymptomatic. The median overall survival for patients with lung cancer is less than 12 months. Important exceptions to these dim statistics exist, however—in particular, the improved survival for patients with early-stage SCLC with systemic therapy, those with NSCLC whose tumors are surgically resectable, and the subset of patients with adenocarcinoma who have mutations in driver oncogenes (e.g., EGFR, ALK) who respond well to inhibitors of these proteins (see later discussion).

As noted above, the clinical course is different for SCLC and NSCLC. For NSCLC, clinical course and survival are a function of the surgical pathologic stage, although it may also be somewhat better for patients with adenocarcinomas that have EGFR or ALK mutations as mentioned above. The staging scheme for NSCLC utilizes the tumor-node-metastasis (TNM) system in order to reflect prognostic subgroups (see Table 53-1 and Chapter 86). Survival improves markedly with surgical resectability (stages I to IIIA). For example, those patients whose disease has not spread to lymph nodes (stage I) have a 5-year survival approaching 50%. Patients with stage II disease (more advanced cancer with either invasion of local structures or involvement of hilar lymph nodes) have a 5-year survival of approximately 30%. Patients with stage IIIA disease (even more advanced local cancer with either invasion of more distant structures or hilar lymph node involvement or less advanced local cancer but with involvement of mediastinal lymph nodes) have a 5-year survival rate of approximately 20% to 25%. Unfortunately, only a small minority of patients present with surgically curable disease.

SCLC differs substantially from NSCLC in how it is staged, being divided into localized and extensive. This is because treatment is defined based on these two subgroups. Before the advent of contemporary chemotherapy, median survival was 1 to 3 months; it has increased severalfold depending on the extent of disease with a median of 18 to 24 months for those with localized disease and 12 to 14 months for those with extensive disease. Five-year survival remains poor (5% to 10%) because of the high probability of metastasis, even among those who present with limited disease.