II. CARCINOMA OF LUNG
A. INTRODUCTION
In 2007, primary carcinoma of the lung affected 114,760 males
and 98,620 females in the United States; 86% die within 5 years of
diagnosis, making it the leading cause of cancer death in both men
and women. The incidence of lung cancer peaks between ages 55 and
65 years. Lung cancer accounts for 29% of all cancer deaths (31% in
men, 26% in women). Lung cancer is responsible for more deaths in
the United States each year than breast cancer, colon cancer, and
prostate cancer combined; more women die each year of lung cancer
than of breast cancer. The age-adjusted lung cancer death rate in
males is decreasing, but in females it is stable or still
increasing. These death rates are related to smoking; smoking
cessation efforts begun 40 years ago in men are largely responsible
for the change in incidence and death rates.
However, women started smoking in substantial numbers about 1015
years later than men; smoking cessation efforts need to increase
for women. The 5-year overall lung cancer survival rate (15%) has
nearly doubled in the past 30 years. The improvement is due to
advances in combined-modality treatment with surgery, radiotherapy,
and chemotherapy. The International Agency for Research on Cancer
estimates that there will be over 1.18 million deaths from lung
cancer worldwide in 2007, which will rise to 10 million deaths per
year by 2030. This represents one lung cancer case for every 3
million cigarettes smoked. Thus, primary carcinoma of the lung is a
major health problem with a generally grim prognosis.
B. PATHOLOGY
The term lung cancer is used for tumors arising from the
respiratory epithelium (bronchi, bronchioles, and alveoli).
Mesotheliomas, lymphomas, and stromal tumors (sarcomas) are
distinct from epithelial lung cancer. Four major cell types make up
88% of all primary lung neoplasms according to the World Health
Organization classification (Table 85-1). These are squamous or
epidermoid carcinoma, small cell (also called oat cell) carcinoma,
adenocarcinoma (including bronchioloalveolar), and large cell
carcinoma. The remainder include undifferentiated carcinomas,
carcinoids, bronchial gland tumors (including adenoid cystic
carcinomas and mucoepidermoid tumors), and rarer tumor types. The
various cell types have different natural histories and responses
to therapy, and thus a correct histologic diagnosis by an
experienced pathologist is the first step to correct treatment. In
the past 25 years, adenocarcinoma has replaced squamous cell
carcinoma as the most frequent histologic subtype, and the
incidence of small cell carcinoma is on the decline.
Table 1.Frequency, Age-Adjusted Incidence, and Survival Rates
for Different Histologic Types of Lung Cancera
Histologic Type of Thoracic MalignancyFrequency, %Age-Adjusted
Rate5-Year Survival Rate (All Stages)
Adenocarcinoma (and all subtypes)32717
Bronchioloalveolar carcinoma31.442
Squamous cell (epidermoid) carcinoma291515
Small cell carcinoma 1895
Large cell carcinoma9511
Carcinoid1.00.583
Mucoepidermoid carcinoma0.190% 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 3050% of cases and response to
combination chemotherapy in 2035% 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 (90% of lung cancers.
Genome-wide approaches are identifying other amplified or mutated
dominant oncogenes that could be important new therapeutic
targets.
b. Inactivation of Tumor-Supressor Genes
A large number of tumor-suppressor genes (recessive oncogenes)
have been identified that are inactivated during the pathogenesis
of lung cancer. This usually occurs by a tumor-acquired
inactivating mutation of one allele [seen, for example, in the p53
and retinoblastoma (RB) tumor-suppressor gene] or tumor-acquired
inactivation of expression by tumor-acquired promoter DNA
methylation (seen, for example, in the case of the p16 and RASSF1A
tumor-suppressor genes), which is then coupled with physical loss
of the other parental allele ("loss of heterozygosity"). This
leaves the tumor cell with only the functionally inactive allele
and thus loss of function of the growth-regulatory tumor-suppressor
gene. Genome-wide approaches have identified many such genes
involved in lung cancer pathogenesis, including p53, RB, RASSF1A,
SEMA3B, SEMA3F, FUS1, p16, LKB1, RAR, and FHIT. Several
tumor-suppressor genes on chromosome 3p appear to be involved in
nearly all lung cancers. Allelic loss for this region occurs very
early in lung cancer pathogenesis, including in histologically
normal smoking-damaged lung epithelium.
c. Autocrine Growth Factors
The large number of genetic and epigenetic lesions shows that
lung cancer, like other common epithelial malignancies, arises as a
multistep process that is likely to involve both carcinogens
causing mutation ("initiation") and tumor promoters. Prevention can
be directed at both processes. Lung cancer cells produce many
peptide hormones and express receptors for these hormones. They can
promote tumor cell growth in an "autocrine" fashion.
Highly carcinogenic derivatives of nicotine are formed in
cigarette smoke. Lung cancer cells of all histologic types (and the
cells from which they are derived) express nicotinic acetylcholine
receptors. Nicotine activates signaling pathways in tumor and
normal cells that block apoptosis. Thus, nicotine itself could be
directly involved in lung cancer pathogenesis both as a mutagen and
tumor promoter.
d. Inherited Predisposition to Lung Cancer
While an inherited predisposition to develop lung cancer is not
common, several features suggest a potential for familial
association. People with inherited mutations in RB (patients with
retinoblastomas living to adulthood) and p53 (Li-Fraumeni syndrome)
genes may develop lung cancer. First-degree relatives of lung
cancer probands have a two- to threefold excess risk of lung cancer
or other cancers, many of which are not smoking-related. An as yet
unidentified gene in chromosome region 6q23 was found to segregate
in families at high risk of developing lung cancer of all
histologic types. Finally, certain polymorphisms of the P450 enzyme
system (which metabolizes carcinogens) or chromosome fragility
(mutagen sensitivity) genotypes are associated with the development
of lung cancer. The use of any of these inherited differences to
identify persons at very high risk of developing lung cancer would
be useful in early detection and prevention efforts.
e. Therapy Targeted at Molecular Abnormalities
A detailed understanding of the molecular pathogenesis should be
applicable to new methods of early diagnosis, prevention, and
treatment of lung cancer. Two examples of this translation involve
EGFR and vascular endothelial growth factor (VEGF). EGFR belongs to
the ERBB (HER) family of protooncogenes, including EGFR (ERBB1),
Her2/neu (ERBB2), HER3 (ERBB3), and HER4 (ERBB4), cell-surface
receptors consisting of an extracellular ligand-binding domain, a
transmembrane structure, and an intracellular tyrosine kinase (TK)
domain. The binding of ligand to receptor activates receptor
dimerization and TK autophosphorylation, initiating a cascade of
intracellular events, leading to increased cell proliferation,
angiogenesis, metastasis, and a decrease in apoptosis (Chap. 80).
Overexpression of EGFR protein or amplification of the EGFR gene
has been found in as many as 70% of NSCLCs.
Activating/oncogenic mutations (usually a missense or a small
deletion mutation) in the TK domain of EGFR have been identified.
These are found most commonly in women, East Asians, patients who
have never smoked, and those with adenocarcinoma and BAC histology.
This is also the group of patients who are most likely to have
dramatic responses to drugs that inhibit TK activation [tyrosine
kinase inhibitors (TKIs)]. EGFR mutations are almost never found in
cancers other than lung cancer, nor in lung cancers that have KRAS
mutations. These EGFR mutations, often associated with
amplification of the EGFR gene, usually confer sensitivity of these
lung cancers to EGFR TKIs (such as gefitinib or erlotinib),
resulting in clinically beneficial tumor responses that
unfortunately are still not permanent. In many cases the
development of EGFR TKI resistance is associated with the
development of another mutation in the EGFR gene (T790M mutation),
or amplification of the c-met oncogene. However, other drugs with
EGFR TKI activity are in development to which the lung cancers with
these resistance mutations will respond as are drugs targeting
c-met or its pathways.
The discovery of EGFR mutation/amplification driving lung cancer
growth and the dramatic response of these tumors to oral EGFR TKI
therapy has prompted a widespread search for other drugs "targeted"
against oncogenic changes in lung cancer. An important example of
another such target is VEGF, which, while not mutated, is
inappropriately produced by lung cancers and stimulates tumor
angiogenesis (Chap. 80). VEGF is often overexpressed in lung
cancer, and the resulting increase in tumor microvessel density
correlates with poor prognosis. A monoclonal antibody to the VEGF
ligand, bevacizumab, has significant antitumor effects when used
with chemotherapy in lung cancer (see below).
f. Molecular Profiles Predict Survival Response
Just as the presence of EGFR TK domain mutations and
amplification is an excellent predictor of response to EGFR TKIs,
molecular predictors of response to standard chemotherapy and other
new targeted agents are being sought. Lung cancers can be
molecularly typed at the time of diagnosis to yield information
that predicts survival and defines agents to which the tumor is
most likely to respond. One example is the identification of
alterations in lung cancer DNA repair pathways that may predict
resistance to chemotherapy.
Patients whose tumors exhibit low activity of the
excision-repair-cross complementation group 1 (ERCC1) proteins
typically have a worse prognosis as they are unable to repair DNA
adducts in the tumor. However, retrospective analysis shows that
when treated with cisplatin, patients with tumors expressing low
levels of ERCC1 activity appear to do better, as they are unable to
repair DNA adducts caused by cisplatin, while patients with high
ERCC1 activity actually do worse with cisplatin-based
chemotherapy.
Although these protein or gene expression "signatures" have yet
to be validated in large prospective studies, it is possible that
such information will allow future therapy to be tailored to the
characteristics of each patient's tumor. Mass spectroscopy-based
proteomic studies have identified unique protein patterns in the
serum of patients, one of which allows for early diagnosis, while
another can predict sensitivity or resistance to drugs. However,
such methods have not been validated and may be difficult to
implement in a patient care setting.
D. CLINICAL MANIFESTATIONS
Lung cancer gives rise to signs and symptoms caused by local
tumor growth, invasion or obstruction of adjacent structures,
growth in regional nodes through lymphatic spread, growth in
distant metastatic sites after hematogenous dissemination, and
remote effects of tumor products (paraneoplastic syndromes).
Although 515% of patients with lung cancer are identified while
they are asymptomatic, usually as a result of a routine chest
radiograph or through the use of screening CT scans, most patients
present with some sign or symptom. Central or endobronchial growth
of the primary tumor may cause cough, hemoptysis, wheeze and
stridor, dyspnea, and postobstructive pneumonitis (fever and
productive cough). Peripheral growth of the primary tumor may cause
pain from pleural or chest wall involvement, dyspnea on a
restrictive basis, and symptoms of lung abscess resulting from
tumor cavitation.
Regional spread of tumor in the thorax (by contiguous growth or
by metastasis to regional lymph nodes) may cause tracheal
obstruction, esophageal compression with dysphagia, recurrent
laryngeal nerve paralysis with hoarseness, phrenic nerve paralysis
with elevation of the hemidiaphragm and dyspnea, and sympathetic
nerve paralysis with Horner's syndrome (enophthalmos, ptosis,
miosis, and ipsilateral loss of sweating). Malignant pleural
effusion often leads to dyspnea. Pancoast's (or superior sulcus
tumor) syndrome results from local extension of a tumor growing in
the apex of the lung with involvement of the eighth cervical and
first and second thoracic nerves, with shoulder pain that
characteristically radiates in the ulnar distribution of the arm,
often with radiologic destruction of the first and second ribs.
Often Horner's syndrome and Pancoast's syndrome coexist. Other
problems of regional spread include superior vena cava syndrome
from vascular obstruction; pericardial and cardiac extension with
resultant tamponade, arrhythmia, or cardiac failure; lymphatic
obstruction with resultant pleural effusion; and lymphangitic
spread through the lungs with hypoxemia and dyspnea. In addition,
BAC can spread transbronchially, producing tumor growing along
multiple alveolar surfaces with impairment of gas exchange,
respiratory insufficiency, dyspnea, hypoxemia, and sputum
production.
Extrathoracic metastatic disease is found at autopsy in >50%
of patients with squamous carcinoma, 80% of patients with
adenocarcinoma and large cell carcinoma, and >95% of patients
with small cell cancer. Lung cancer metastases may occur in
virtually every organ system. Common clinical problems related to
metastatic lung cancer include brain metastases with headache,
nausea, and neurologic deficits; bone metastases with pain and
pathologic fractures; bone marrow invasion with cytopenias or
leukoerythroblastosis; liver metastases causing liver dysfunction,
biliary obstruction, anorexia, and pain; lymph node metastases in
the supraclavicular region and occasionally in the axilla and
groin; and spinal cord compression syndromes from epidural or bone
metastases. Adrenal metastases are common but rarely cause adrenal
insufficiency.
Paraneoplastic syndromes are common in patients with lung cancer
and may be the presenting finding or first sign of recurrence. In
addition, paraneoplastic syndromes may mimic metastatic disease
and, unless detected, lead to inappropriate palliative rather than
curative treatment. Often the paraneoplastic syndrome may be
relieved with successful treatment of the tumor. In some cases, the
pathophysiology of the paraneoplastic syndrome is known,
particularly when a hormone with biologic activity is secreted by a
tumor. However, in many cases the pathophysiology is unknown.
Systemic symptoms of anorexia, cachexia, weight loss (seen in 30%
of patients), fever, and suppressed immunity are paraneoplastic
syndromes of unknown etiology. Endocrine syndromes are seen in 12%
of patients: hypercalcemia and hypophosphatemia resulting from the
ectopic production by squamous tumors of parathyroid hormone (PTH)
or, more commonly, PTH-related peptide; hyponatremia with the
syndrome of inappropriate secretion of antidiuretic hormone or
possibly atrial natriuretic factor by small cell cancer; and
ectopic secretion of ACTH by small cell cancer. ACTH secretion
usually results in additional electrolyte disturbances, especially
hypokalemia, rather than the changes in body habitus that occur in
Cushing's syndrome from a pituitary adenoma.
Skeletalconnective tissue syndromes include clubbing in 30% of
cases (usually non-small cell carcinomas) and hypertrophic
pulmonary osteoarthropathy in 110% of cases (usually
adenocarcinomas), with periostitis and clubbing causing pain,
tenderness, and swelling over the affected bones and a positive
bone scan. Neurologic-myopathic syndromes are seen in only 1% of
patients but are dramatic and include the myasthenic Eaton-Lambert
syndrome and retinal blindness with small cell cancer, while
peripheral neuropathies, subacute cerebellar degeneration, cortical
degeneration, and polymyositis are seen with all lung cancer
types.
Many of these are caused by autoimmune responses such as the
development of anti-voltage-gated calcium channel antibodies in the
Eaton-Lambert syndrom.. Coagulation, thrombotic, or other
hematologic manifestations occur in 18% of patients and include
migratory venous thrombophlebitis (Trousseau's syndrome),
nonbacterial thrombotic (marantic) endocarditis with arterial
emboli, disseminated intravascular coagulation with hemorrhage,
anemia, granulocytosis, and leukoerythroblastosis. Thrombotic
disease complicating cancer is usually a poor prognostic sign.
Cutaneous manifestations such as dermatomyositis and acanthosis
nigricans are uncommon (1%), as are the renal manifestations of
nephrotic syndrome or glomerulonephritis (1%).
E. DIAGNOSIS AND STAGING
Screening
Most patients with lung cancer present with advanced disease,
raising the question of whether screening would detect these tumors
at an earlier stage when they are theoretically more curable. The
role of screening high-risk patients (for example current or former
smokers >50 years of age) for early stage lung cancers is
debated. Results from five randomized screening studies in the
1980s of chest x-rays with or without cytologic analysis of sputum
did not show any impact on lung cancerspecific mortality from
screening high-risk patients, although earlier-stage cancers were
detected in the screened groups.
These studies have been criticized for their design and
statistical analyses, but they led to current recommendations not
to use these tools to screen for lung cancer. However, low-dose,
noncontrast, thin-slice, helical, or spiral CT has emerged as a
possible new tool for lung cancer screening. Spiral CT is a scan in
which only the pulmonary parenchyma is examined, thus negating the
use of intravenous contrast and the necessity of a physician being
present at the exam. The scan can usually be done quickly (within
one breath) and involves low doses of radiation. In a nonrandomized
study of current and former smokers from the Early Lung Cancer
Action Project (ELCAP), low-dose CT was shown to be more sensitive
than chest x-ray for detecting lung nodules and lung cancer in
early stages. Survival from date of diagnosis is also long (10-year
survival predicted to be 92% in screening-detected stage I NSCLC
patients). Other nonrandomized CT screening studies of asymptomatic
current or former smokers also found that early lung cancer cases
were diagnosed more often with CT screening than predicted by
standard incidence data. However, no decline in the number of
advanced lung cancer cases or deaths from lung cancer was noted in
the screened group. Thus, spiral CT appears to diagnose more lung
cancer without improving lung cancer mortality. Concerns include
the influence of lead-time bias, length-time bias, and
over-diagnosis (cancers so slow-growing that they are unlikely to
cause the death of the patient).
Over-diagnosis is a well-established problem in prostate cancer
screening, but it is surprising that some lung cancers are not
fatal. However, many of the small adenocarcinomas found as "ground
glass" opacities on screening CT appear to have such long doubling
times (>400 days) that they may never harm the patient. While CT
screening will detect lung cancer in 14% of the patients screened
over a 5-year period, it also detects a substantial number of
false-positive lung lesions (ranging from 25 to 75% in different
series) that need follow-up and evaluation. The appropriate
management of these small lesions is undefined.
Unnecessary treatment of these patients may include thoracotomy
and lung resection, thus adding to the cost, mortality, and
morbidity of treatment. A large, randomized trial of CT screening
for lung cancer (National Lung Cancer Screening Trial) involving
~55,000 individuals has completed accrual and will provide
definitive data in the next several years on whether screening
reduces lung cancer mortality. Until these results become
available, routine CT screening for lung cancer cannot be
recommended for any risk group. For those patients who want to be
screened, physicians need to discuss the possible benefits and
risks of such screening, including the risk of false-positive scans
that could result in multiple follow-up CTs and possible biopsies
for a malignancy that may not be life-threatening.
Establishing a Diagnosis of Lung Cancer
Once signs, symptoms, or screening studies suggest lung cancer,
a tissue diagnosis must be established. Tumor tissue can be
obtained by a bronchial or transbronchial biopsy during fiberoptic
bronchoscopy; by node biopsy during mediastinoscopy; from the
operative specimen at the time of definitive surgical resection; by
percutaneous biopsy of an enlarged lymph node, soft tissue mass,
lytic bone lesion, bone marrow, or pleural lesion; by fine-needle
aspiration of thoracic or extrathoracic tumor masses using CT
guidance; or from an adequate cell block obtained from a malignant
pleural effusion. In most cases, the pathologist should be able to
make a definite diagnosis of epithelial malignancy and distinguish
small cell from non-small cell lung cancer.
Staging Patients with Lung Cancer
Lung cancer staging consists of two parts: first, a
determination of the location of tumor (anatomic staging) and,
second, an assessment of a patient's ability to withstand various
antitumor treatments (physiologic staging). In a patient with
NSCLC, resectability (whether the tumor can be entirely removed by
a standard surgical procedure such as a lobectomy or
pneumonectomy), which depends on the anatomic stage of the tumor,
and operability (whether the patient can tolerate such a surgical
procedure), which depends on the cardiopulmonary function of the
patient, are determined.
1. Non-Small Cell Lung Cancer
The TNM International Staging System should be used for cases of
NSCLC, particularly in preparing patients for curative attempts
with surgery or radiotherapy (Table 2). The various T (tumor size),
N (regional node involvement), and M (presence or absence of
distant metastasis) factors are combined to form different stage
groups. At presentation, approximately one-third of patients have
disease localized enough for a curative attempt with surgery or
radiotherapy (patients with stage I or II disease and some with
stage IIIA disease), one-third have distant metastatic disease
(stage IV disease), and one-third have local or regional disease
that may or may not be amenable to a curative attempt (some
patients with stage IIIA disease and others with stage IIIB
disease) (see below). This staging system provides useful
prognostic information.
Table 2. Tumor, Node, Metastasis International Staging System
for Lung CancerStageTNM Descriptors5-Year Survival Rate, %
Clinical StageSurgical-Pathologic Stage
IAT1 N0 M06167
IBT2 N0 M03857
IIAT1 N1 M03455
IIBT2 N1 M02439
IIBT3 N0 M02238
IIIAT3 N1 M0925
T123 N2 M01323
IIIBT4 N012 M07
