Chapter 085. Neoplasms of the Lung (Part 2) Major treatment decisions are made on the basis of whether a tumor is classified as a small cell lung carcinoma (SCLC) or as one of the non-small cell lung cancer (NSCLC) varieties (squamous, adenocarcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mixed versions of these). The histologic distinctions between SCLC and NSCLC include the following: SCLC has scant cytoplasm, small hyperchromatic nuclei with fine chromatin pattern and indistinct nucleoli with diffuse sheets of cells, while NSCLC has abundant cytoplasm, pleomorphic nuclei with coarse chromatin pattern, prominent nucleoli, and glandular or squamous architecture. Among the molecular distinctions, SCLC displays neuroendocrine properties absent in NSCLCs, production of specific peptide hormones [such as adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP), atrial natriuretic factor (ANF), gastrin-releasing peptide (GRP)] and differences in oncogene and tumor-suppressor gene changes (SCLCs have RB mutations in 90% and p16 abnormalities in 10% but never have KRAS or EGFR mutations, while NSCLCs have RB mutations in only 20%, p16 changes in 50%, KRAS mutations in 30%, and EGFR mutations in ~10%). Both types have frequent p53 mutations (>70% in SCLC and >50% in NSCLC), 3p allele loss (>90% in both), telomerase expression (>90% in both), and tumor- acquired promoter methylation in multiple genes (>80% in both, often involving the same genes, including RASSF1A). SCLCs are initially very responsive to combination chemotherapy (>70% responses, with 30% complete responses) and to radiotherapy (>90% responses); however, most SCLCs ultimately relapse. By contrast, NSCLCs have objective tumor shrinkage following radiotherapy in 30– 50% of cases and response to combination chemotherapy in 20–35% of cases. At presentation, SCLCs usually have already spread such that surgery is unlikely to be curative and, given their responsiveness to chemotherapy, are managed primarily by chemotherapy with or without radiotherapy. Chemotherapy clearly provides symptom relief and survival advantage. By contrast, NSCLCs that are clinically localized at the time of presentation may be cured with either surgery or radiotherapy. The beneficial role of chemotherapy in NSCLC is in palliation of symptoms and improving survival modestly. Although it is important to differentiate whether a tumor is SCLC or NSCLC for both prognostic and therapeutic reasons, it is less important to identify the histologic subtypes of NSCLC. Stage for stage, the histology of NSCLC is not an important prognostic factor, and in the past the different subtypes of NSCLC were rarely treated differently. However, lung adenocarcinomas (often with bronchioloalveolar features) may be responsive to therapy aimed at the epidermal growth factor receptor (EGFR) (see below). In addition, patients with squamous cell carcinoma may not be appropriate candidates for antiangiogenic therapy due to an increased risk of bleeding (see below). Eighty-five percent of patients with lung cancer of all histologic types are current or former cigarette smokers. Of the annual 213,380 new cases of lung cancer, ~50% develop in former smokers. With increased success in smoking cessation efforts, the number of former smokers will grow, and these individuals will be important candidates for early detection and chemoprevention efforts. All histologic types of lung cancer are due to smoking. However, lung cancer can also occur in individuals who have never smoked. By far the most common form of lung cancer arising in lifetime nonsmokers, in women, and in young patients (<45 years) is adenocarcinoma. However, in nonsmokers with adenocarcinoma involving the lung, the possibility of other primary sites should be considered. Squamous and small cell cancers usually present as central masses with endobronchial growth, while adenocarcinomas and large cell cancers tend to present as peripheral nodules or masses, frequently with pleural involvement. Squamous and large cell cancers cavitate in 10–20% of cases. Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma that grows along the alveoli without invasion and can present radiographically as a single mass; as a diffuse, multinodular lesion; as a fluffy infiltrate; and on screening CT scans as a "ground glass" opacity. The male to female ratio is 1:1, and while BAC can be associated with smoking, it is often found in nonsmokers. Histologically pure BAC is relatively rare. More common is adenocarcinoma with BAC features. BAC may present in a mucinous form, which tends to be multicentric, and a nonmucinous form, which tends to be solitary. Many of the EGFR mutations found in nonsmoking lung cancers occur in adenocarcinomas with BAC histologic features. Etiology Most lung cancers are caused by carcinogens and tumor promoters inhaled via cigarette smoking. The prevalence of smoking in the United States is 28% for males and 25% for females, age 18 years or older; 38% of high school seniors smoke. The relative risk of developing lung cancer is increased about thirteenfold by active smoking and about 1.5-fold by long-term passive exposure to cigarette smoke. Chronic obstructive pulmonary disease, which is also smoking-related, further increases the risk of developing lung cancer. The lung cancer death rate is related to the total amount (often expressed in "cigarette pack-years") of cigarettes smoked, such that the risk is increased 60- to 70-fold for a man smoking two packs a day for 20 years as compared with a nonsmoker. Conversely, the chance of developing lung cancer decreases with cessation of smoking but may never return to the nonsmoker level. The increase in lung cancer rate in women is also associated with a rise in cigarette smoking. Women have a higher relative risk per given exposure than men (~1.5-fold higher). This sex difference may be due to a greater susceptibility to tobacco carcinogens in women, although the data are controversial. . Chapter 085. Neoplasms of the Lung (Part 2) Major treatment decisions are made on the basis of whether a tumor is classified as a small cell lung carcinoma (SCLC) or as one of the non-small. smoking-related, further increases the risk of developing lung cancer. The lung cancer death rate is related to the total amount (often expressed in "cigarette pack-years") of cigarettes. are clinically localized at the time of presentation may be cured with either surgery or radiotherapy. The beneficial role of chemotherapy in NSCLC is in palliation of symptoms and improving