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

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.