53 clinical aspects of lung cancer

Transcription

53
CLINICAL ASPECTS OF
LUNG CANCER
GERARD A. SILVESTRI, MD, MS • NICHOLAS J. PASTIS, MD •
NICHOLE T. TANNER, MD, MSCR • JAMES R. JETT, MD
INTRODUCTION
SCREENING FOR LUNG CANCER
PRESENTATION
LUNG CANCER STAGING
NONINVASIVE STAGING
TECHNIQUES
Chest Radiography
Chest Computed Tomography
Positron Emission Tomography
Magnetic Resonance Imaging
Search for Metastatic Disease
Summary
INVASIVE DIAGNOSTIC AND STAGING
TECHNIQUES
Sputum Cytology
Transthoracic Needle Aspiration
Fiberoptic Bronchoscopy
Endoscopic Ultrasound
Endobronchial Ultrasound
Mediastinoscopy
TREATMENT OF LUNG CANCER
Prognostic Factors for Lung Cancer
Non–Small Cell Lung Cancer Treatment
by Stage
Small Cell Lung Cancer
INTRODUCTION
Lung cancer is the most common cause of cancer deaths
worldwide. In the United States, lung cancer accounted for
more than 250,000 cases of cancer and greater than
150,000 deaths from cancer in 2013.1 Chapter 52 is dedicated to the epidemiology of lung cancer but some of the
information found therein is worth repeating. For example,
the number of lung cancer deaths each year exceeds the
number of cancer deaths from breast, colon, and prostate
cancer combined. A common misconception among the
general public is that breast cancer accounts for more
cancer deaths in women. However, lung cancer is now the
greatest cancer killer of women and will account for 25%
of cancer-related deaths among women in the United
States. Particularly alarming is the fact that young women
are in the fastest rising demographic of new cigarette
smokers in the United States. Many have clearly made the
association between weight control and cigarette smoking.
This will have effects on the prevalence of lung cancer in
the decades to come.
One of the more disturbing trends in lung cancer is the
explosion in rates of lung cancer in countries of the developing world. In 1985, it was estimated that there were
921,000 lung cancer deaths worldwide—an increase of
17% from 1980.2 In 2011, lung cancer accounted for 13%
of cases (1.6 million) and 18% of deaths (1.4 million)
worldwide.1 The International Agency for Research on
Cancer in France found that the rates of lung cancer in
Africa in the early 1990s were similar to those in the United
States in the 1930s, at about 5 per 100,000. By 1999, the
rate of lung cancer in males in developing countries was 14
in 100,000 and on the rise, compared with a rate of 71 in
100,000 in developed countries, which continues to decline.
These rates may actually be underestimates of the true
940
PALLIATIVE CARE
SPECIAL CONSIDERATIONS IN LUNG
CANCER
Superior Sulcus Tumors and Pancoast
Syndrome
Superior Vena Cava Syndrome
PARANEOPLASTIC SYNDROMES
Musculoskeletal Effects
Hematologic Effects
Hypercalcemia
Syndrome of Inappropriate Antidiuretic
Hormone Secretion
Ectopic Corticotropin Syndrome
Neurologic Effects
rates of lung cancer, because many cases may go undiagnosed or underreported in areas where health care is not
readily available.2 The seriousness of this problem is exemplified in China, where it is estimated that nearly 800,000
Chinese men died of lung cancer in 1998.2 It remains
imperative that the medical community devotes much of its
educational efforts and resources to the elimination of cigarette smoking worldwide, which would nearly eliminate the
development of lung cancer (see also Chapter 46).
This chapter reviews the current strategies for the diagnosis, reviews the staging system, and describes the current
treatment of lung cancer. As much as possible, evidencebased review of the best currently available literature has
been included. The role of the pulmonologist is described for
every aspect of lung cancer care, from diagnosis to staging
to caring for the complications of the disease itself and the
complications of cancer treatment.
SCREENING FOR LUNG CANCER
The U.S. Preventive Services Task Force now recommends
screening for lung cancer with low dose computed tomography (CT) in high-risk patients (see Chapter 18). Before
2013, there was insufficient evidence to support screening
for lung cancer.3 For example, the 2004 U.S. Preventive Services Task Force position was based on the results of five
randomized, controlled trials that suggested that neither
chest radiography nor sputum cytology satisfies the primary
criterion of a beneficial screening test: a reduction in lung
cancer mortality.4-6 One deficiency was that most of these
studies did not include a “no screening” arm. Others arguably had an inadequate sample size. In 2011, the results of
the lung arm of the National Cancer Institute’s Prostate,
Lung, Colorectal, and Ovarian Trial demonstrated that, in
53 • Clinical Aspects of Lung Cancer
a randomized trial of chest radiography versus no screening
in a low-risk population of both genders, there was no
reduction in mortality from lung cancer in the chest radiography screened group compared with usual care.7
Chest CT has been shown to be much more sensitive for
detecting pulmonary nodules than the standard chest
radiograph. There have been a number of single-arm
screening trials utilizing low-dose computed tomography
(LDCT), defined as a single breath-hold scan that exposes
the patient to a five to six times smaller radiation dose than
a standard CT scan, with or without sputum cytology.4,8-13
Although these trials consistently showed that chest CT
detects more lung cancers than chest radiography, they
were not designed to provide information on mortality
benefit. Trials without control arms can be subject to different potential sources of bias.10,14 Lead-time bias is the detection of tumors earlier in their course; length-time bias is the
greater detection of less aggressive, slower-growing tumors
than more aggressive, faster-growing tumors; and overdiagnosis is the detection of tumors that would otherwise never
cause symptoms or death.
The National Lung Cancer Screening Trial (NLST) is the first
large-scale randomized trial to demonstrate a convincing
mortality benefit for LDCT lung cancer screening in highrisk individuals. The trial included 33 centers across the
United States. Eligible participants were between ages 55
and 74 years at the time of randomization, had a history of
at least 30 pack-years of cigarette smoking, and, if former
smokers, had quit within the past 15 years.15 A total of
53,454 persons were enrolled; 26,722 were randomly
assigned to screening with LDCT and 26,732 to screening
with chest radiography. Any noncalcified nodule found on
LDCT measuring at least 4 mm in any diameter and chest
radiographic images with any noncalcified nodule or mass
were classified as positive. The LDCT-screened group had a
substantially higher rate of positive screening tests compared with the radiography group (round 1: 27.3% vs.
9.2%; round 2: 27.9% vs. 6.2%; round 3: 16.8% vs. 5%).
Overall, 39.1% of participants in the LDCT group and 16%
in the radiography group had at least one positive screening
result. Of those with a positive screening result, the falsepositive rate was 96.4% in the LDCT group and 94.5% in
the radiography group.
In the LDCT group, 649 cancers were diagnosed after a
positive screening test, 44 after a negative screening test,
and 367 among participants who either missed the screening or received the diagnosis after the completion of the
screening phase. In the radiography group, 279 cancers
were diagnosed after a positive screening test, 137 after a
negative screening test, and 525 among participants who
either missed the screening or received the diagnosis after
the completion of the screening phase. There were a total
of 356 deaths from lung cancer in the LDCT group and 443
in the chest radiography group, with a relative reduction in
the rate of death from lung cancer of 20% with LDCT
screening. Overall mortality was reduced by 6.7%. The
number needed to screen with LDCT to prevent 1 death
from lung cancer was 320, which is comparable to the
numbers in studies on screening mammography for breast
cancer in women older than 50 years.
One of the concerns with using LDCT for lung cancer
screening is the high rate of positive test results necessitat-
ing further workup. Investigators from the NELSON study
demonstrated that this can be overcome by using semiautomated volumetry software to measure diameter and
volume doubling time.16 Growth was defined as a change in
volume between the first and the second scan of 25% or
greater. Nodules meeting growth criteria were then classified into three categories based on volume doubling time
(<400 days; 400–600 days; >600 days). This approach to
nodule management resulted in a decrease in the rate of
positive test results at baseline from 30% to 2%. The final
results regarding the reduction in mortality from lung
cancer in this trial are pending.
Despite the impressive results from NLST in high-risk
adults, the ability to generalize the results to other populations has been questioned. Participants in the NLST were
enrolled in urban tertiary care hospitals with expertise in
all aspects of cancer care. LDCT studies were interpreted by
dedicated chest radiologists with expertise in characterizing
nodules and providing appropriate recommendations for
follow-up. As a result, few patients required further invasive
testing, and radiographic follow-up was sufficient for many.
In contrast, community practice gives rise to the potential for considerable variation in the management of solitary pulmonary nodules identified by screening LDCT. One
study demonstrated a twofold variation among geographic
regions in use of CT-guided biopsy, ranging from 14.7 to
36.2 per 100,000 adults. This substantial variation in the
management of solitary pulmonary nodules may lead to an
increased number of invasive procedures with risk of harm.
For instance, complications from transthoracic biopsies
include a 1% rate of bleeding (with one third of affected
patients requiring transfusion) and a 15% rate of pneumothorax. More than 6% of CT-guided biopsies result in a
pneumothorax requiring chest tube drainage, a clinically
important complication that results in pain, serial imaging
with radiation exposure, and hospitalization. Older patients
and those with chronic obstructive pulmonary disease (COPD)
have an increased risk of biopsy-related complications that
can result in longer length of hospital stay, contributing
both to increased cost and higher rates of respiratory failure
that can affect long-term health.17-19
Another difference between the results of the NLST and
community practice is that the mortality from lung cancer
surgery was 1% in the NLST, whereas the national average
is between 3% and 5% for a lobectomy. Whereas NLST participants were allowed to choose where they had their evaluation and management for screen-detected nodules, many
were managed at an NLST site with high volume and dedicated thoracic surgery support, both of which have been
shown to have better outcomes.20,21 Even though 70 years
is the average age at lung cancer diagnosis, only 9% of the
NLST study population was older than age 70. The patients
enrolled in NLST were younger and healthier than persons
who would participate in a broad-based lung cancer screening. Participants had to be medically fit to undergo surgery.
Those screened in the NLST were also less likely to be
current smokers, less ethnically diverse, and more educated
than the general U.S. population.22 These differences follow
the healthy volunteer effect of screening trials in which
there is a self-selection of persons who are better educated
and more health-conscious and who have better access to
medical care.23
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PART 3 • Clinical Respiratory Medicine
The evidence of the NLST contributed to a systematic
review that serves as the basis for a multisociety recommendation for screening in those people meeting the NLST
entry criteria.24 The caveat to the recommendations is that
screening should only be done in those centers with multidisciplinary groups capable of providing comprehensive
care as was present in the trial. Based largely in part on the
results of the NLST, in 2013, the U.S. Preventive Services
Task Force published a draft recommendation giving lung
cancer screening a grade B recommendation (moderate
certainty that annual screening for lung cancer with LDCT
is of moderate net benefit in high-risk asymptomatic
persons).25 The U.S. Preventive Services Task Force found
there to be adequate evidence to screen asymptomatic
patients aged 55 to 79 years with significant tobacco use
history. Their assessment was that the moderate net benefit
of screening depends on two factors: (1) the accuracy of
image interpretation would be comparable to that in the
NLST and (2) most false-positive could be handled without
invasive procedures. 25
There may be potential barriers to lung cancer screening,
especially in current smokers. In one study, current smokers
were less likely to believe that early cancer detection would
result in a good chance of survival. Current smokers are
also less likely to consider CT screening for lung cancer
(71.2%) than are never smokers (87.6%). In addition, only
half of the current smokers surveyed would opt for surgical
resection of a screening-diagnosed cancer.26 Finally, it is
significant that smokers make up 31% of the population
below the poverty line compared with 20% of those at or
above the poverty line27; as a result, smokers are likely to be
a target population more difficult to reach for large-scale
screening in the community.
PRESENTATION
Unfortunately, the symptoms of lung cancer can be nonspecific and variable, thereby delaying diagnosis and frequently
leading to an advanced stage at the time of diagnosis. The
focus of an initial patient evaluation should include signs
and symptoms related to the following: local tumor effects,
extension of disease into the thoracic cavity, radiologic correlation, paraneoplastic syndromes, and distant metastatic
disease. Whereas only 40% of patients with lung cancer in
a screened high-risk outpatient population had symptoms,
98% of patients in a hospitalized population presented with
symptoms.28,29 In general, only approximately one fourth
of patients are asymptomatic at the time lung cancer
is diagnosed, and these patients are more likely to have
less advanced disease.30 Table 53-1 displays some of the
common symptoms associated with the presentation of
lung cancer. Most are nonspecific; however, some clues can
be gained from the history, thus raising the clinician’s suspicion that lung cancer is present.
Although many smokers cough, lung cancer patients
usually admit to a change in the character of their cough.
The cough can increase in frequency or strength, or may
not be relieved with local measures. Chest pain can be
present in 25% to 50% of patients at the time of presentation for evaluation for lung cancer.28,31 The pain is generally
dull in nature, tends to be persistent, remains in the same
Table 53-1
Carcinoma
Presenting Symptoms with Bronchogenic
Symptoms and Signs
Frequency, %
Cough
Weight loss
Dyspnea
8–75
0–68
3–60
Chest pain
Hemoptysis
Bone pain
Clubbing
20–49
6–35
6–25
0–20
Fever
Hoarseness
Weakness
0–20
2–18
0–10
Superior vena cava obstruction
Dysphagia
0–4
0–2
Wheezing and stridor
0–2
Modified from references 31 and 290 to 295.
location, and is not relieved with local measures. Chest pain
is usually related to involvement of the pleura but can be
related to extension into the mediastinum or chest wall.
However, chest pain in and of itself does not preclude the
patient from consideration for surgery with curative intent.
Dyspnea is frequently a complaint of patients who present
with bronchogenic carcinoma, noted in half of all new
patients at presentation.28 A partial list of the reasons for
dyspnea related to lung cancer includes pulmonary embolism, superior vena cava (SVC) syndrome, deconditioning,
reactive airway disease, endobronchial obstruction with
tumor, prior obstructive pneumonia, hemoptysis, hemorrhage, malignant pleural effusion, and extrinsic compression of the airway by tumor.
Hemoptysis in a smoker should raise suspicion of lung
cancer. Hemoptysis can present as blood streaking of the
sputum and can be noted over a lengthy period of time
before presentation to the physician’s office because the
patient attributes it to smoking-related bronchitis. The clinician should not be led astray, even if the chest radiograph
is normal, because up to 5% of patients with hemoptysis
and a smoking history and a normal radiograph can harbor
lung cancer.32 Because of the vascular nature of lung cancer,
patients can also present with massive hemoptysis.
Weight loss, a nonspecific symptom, in the right clinical
setting should raise the suspicion of both lung cancer and
metastatic disease. Weight loss alone has been correlated
with an advanced presentation and poor outcome in lung
cancer cases.
In summary, patients with lung cancer can present
asymptomatically or with relatively nonspecific symptoms
of underlying pulmonary disease. There are often clues in
the history that should alert the clinician that lung cancer
is a possibility and further investigation is warranted.
LUNG CANCER STAGING
Perhaps the most critical role of the pulmonologist in the
management of lung cancer is in the diagnostic and staging
evaluation of the patient. Accurately staging patients with
newly diagnosed lung cancer is critical because staging dictates the patient’s treatment options and predicts survival.
It is intuitive that early-stage disease has a much better
survival than late-stage disease. What may not be so obvious
is that simple staging procedures are available to the diagnostician that can help stage patients accurately. The treatment options for lung cancer have now evolved so that
treatment for patients in different stages is vastly different.
In general, stage I (early-stage lung cancer) is treated with
surgery alone. Stage II lung cancer (a less common stage,
intermediate between early and locally advanced) is treated
with surgery followed by adjuvant chemotherapy. Stage
IIIA and B (locally advanced lung cancer) is treated with a
combination of chemotherapy and radiotherapy, and stage
IV (metastatic disease) is treated with chemotherapy alone.
However, there are important exceptions to these general
rules that are discussed later in this chapter.
The staging of non–small cell lung cancer (NSCLC) using
the tumor-node-metastasis (TNM) classification underwent a
major revision in 2007.33,34 The new staging system is
remarkable in that it is based on more than 100,000 cases
of lung cancer from 23 institutions, 12 countries, and 3
continents. The data are robust, internally validated, and
externally validated against the Surveillance Epidemiology
and End Results cancer registry.33 Tables 53-2 and 53-3
show the current TNM descriptors and stage groupings.
There are several important changes adopted in the
2007 revision. The main modifications are in the T and M
classification; the N status remains the same. Within the T
classification, tumor size was found to be an important
prognosticator and the T factor was subdivided based upon
five different size criteria. Because survivorship was better
than previously thought, a primary tumor with satellite
nodules in the same lobe was reclassified from T4 to T3 and
a tumor with additional nodules in a different lobe of the
ipsilateral lung was moved from an M1 designation to T4.
This change in classification and stage allows more patients
to be considered for surgery. Malignant pleural effusion was
reclassified from T4 (or stage IIIB) disease to M1 disease
because the survival of patients in this group was found to
resemble the survival of those with metastatic disease more
closely than those with locally advanced disease. Another
significant change is that the M status is now split into M1a
(metastatic disease confined to the chest) and M1b (extrathoracic metastatic disease) because survival was found to
be better in those patients with metastatic disease confined
to the thorax compared with those with extrathoracic
metastases.
Whereas the TNM staging system is applied to NSCLC, a
more simplified version is employed for patients with small
cell lung cancer (SCLC). In this classification, patients are
classified as having limited or extensive disease. Limited
disease (LD) is disease limited to one hemithorax, although
it can include supraclavicular and mediastinal lymphadenopathy; extensive disease (ED) is any disease outside of the
hemithorax. The implication in this classification is that LD
is treated with chemotherapy and radiotherapy and ED is
treated with chemotherapy alone.35 Malignant pleural effusion can technically be categorized as LD in the staging
classification for SCLC if the patient otherwise meets criteria. However, for all intents and purposes, patients with
Table 53-2 Tumor-Node-Metastasis (TNM) Descriptors
in the Revised 7th Edition of the TNM Classification of
Lung Cancer
T (PRIMARY TUMOR)
TX
T0
Tis
T1
T1a
T1b
T2
T2a
T2b
T3
T4
Primary tumor cannot be assessed, or tumor proven by the
presence of malignant cells in sputum or bronchial
washings but not visualized by imaging or bronchoscopy
No evidence of primary tumor
Carcinoma in situ
Tumor ≤ 3 cm in greatest dimension, surrounded by lung
or visceral pleura, without bronchoscopic evidence of
invasion more proximal than the lobar bronchus (i.e., not
in the main bronchus)*
Tumor ≤ 2 cm in greatest dimension
Tumor > 2 cm but ≤ 3 cm in greatest dimension
Tumor >3 cm but ≤ 7 cm or tumor with any of the
following features (T2 tumors with these features are
classified T2a if <5 cm)
Involves main bronchus, ≥ 2 cm distal to the carina
Invades visceral pleura
Associated with atelectasis or obstructive pneumonitis that
extends to the hilar region but does not involve the
entire lung
Tumor >3 cm but ≤ 5 cm in greatest dimension
Tumor >5 cm but ≤ 7 cm in greatest dimension
Tumor > 7 cm or one that directly invades any of the
following: chest wall (including superior sulcus tumors),
diaphragm, phrenic nerve, mediastinal pleura, parietal
pericardium; or tumor in the main bronchus < 2 cm distal
to the carina* but without involvement of the carina; or
associated atelectasis or obstructive pneumonitis of the
entire lung or separate tumor nodule(s) in the same lobe
Tumor of any size that invades any of the following:
mediastinum, heart, great vessels, trachea, recurrent
laryngeal nerve, esophagus, vertebral body, carina;
separate tumor nodule(s) in a different ipsilateral lobe
N (REGIONAL LYMPH NODES)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar
lymph nodes and intrapulmonary nodes, including
involvement by direct extension
N2
Metastasis in ipsilateral mediastinal and/or subcarinal
lymph node(s)
N3
Metastasis in contralateral mediastinal, contralateral hilar,
ipsilateral or contralateral scalene, or supraclavicular
lymph node(s)
M (DISTANT METASTASIS)
MX
M0
M1
M1a
M1b
Distant metastasis cannot be assessed
No distant metastasis
Distant metastasis
Separate tumor nodule(s) in a contralateral lobe; tumor
with pleural nodules or malignant pleural (or pericardial)
effusion†
Distant metastasis
*The uncommon superficial spreading tumor of any size with its invasive
component limited to the bronchial wall, which may extend proximally
to the main bronchus, is also classified at T1.
†
Most pleural (and pericardial) effusions with lung cancer are due to tumor.
In a few patients, however, multiple cytopathologic examinations of
pleural (pericardial) fluid are negative for tumor, and the fluid is
nonbloody and is not an exudate. Where these elements and clinical
judgment dictate that the effusion is not related to the tumor, the
effusion should be excluded as a staging element and the patient should
be classified as T1, T2, T3, or T4.
From Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer
Staging Project. J Thorac Oncol 2:709, 2007.
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Table 53-3 Stage Grouping Comparisons: AJCC Staging
Manual 6th versus 7th Edition Descriptors, T and M
Categories, and Stage Groupings
NONINVASIVE STAGING
TECHNIQUES
T and M Descriptor
(6th edition)
T and M
Descriptor
(7th edition)
N0
N1
N2
N3
T1 (≤2 cm)
T1a
IA
IIA
IIIA
IIIB
T1 (>2 to 3 cm)
T1b
IA
IIA
IIIA
IIIB
T2 (≤5 cm)
T2a
IB
IIA
IIIA
IIIB
T2 (>5 to 7 cm)
T2b
IIA
IIB
IIIA
IIIB
T2 (>7 cm)
T3
IIB
IIIA
IIIA
IIIB
T3 (invasion)
T3
IIB
IIIA
IIIA
IIIB
T4 (same lobe nodules)
T4 (extension)
T3
T4
IIB
IIIA
IIIA
IIIA
IIIA
IIIB
IIIB
IIIB
M1 (ipsilateral lung)
T4 (pleural effusion)
T4
M1a
IIIA
IV
IIIA
IV
IIIB
IV
IIIB
IV
M1 (contralateral lung)
M1 (distant)
M1a
M1b
IV
IV
IV
IV
IV
IV
IV
IV
Bold font indicates a change from the sixth edition for a particular TNM
category.
From Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer
Staging Project: Proposals for the revision of the TNM stage groupings in
the forthcoming (seventh) edition of the TNM classification of malignant
tumours. J Thorac Oncol 2:706-714, 2007.
malignant pleural effusions and SCLC have the same characteristics as those with ED, and the large cooperative group
trials have treated them as such.
Some important nuances to staging are described in
detail later in this chapter. However, there are certain tenets
of staging that must be emphasized. Before classifying a
patient within a certain stage, the clinician should make
every effort to verify any noninvasive radiologic findings
with tissue confirmation of malignancy. This is particularly
important when surgical resection would be precluded
based on noninvasive radiologic tests. Thus a patient who
would otherwise be resectable except for a single abnormality suspicious for metastasis should have tissue confirmation of that abnormality before being deemed unresectable.
As is pointed out later in this chapter, no noninvasive radiologic study is infallible. In studies of the mediastinum, falsepositive findings range from 12% in positron emission
tomography (PET) scans to nearly 20% in CT scans (eFigs.
53-1 and 53-2) with lower false-positive findings using
integrated PET-CT, at the cost of lower sensitivity.36,37 Therefore reliance on the scan alone to predict malignancy is
simply not appropriate.
Staging can be accomplished by a number of noninvasive
and invasive studies. The choice of the most appropriate
study rests with the clinician and is based on how the
patient presents. Some patients—for example, those with
isolated solitary pulmonary nodules—may be referred for
immediate surgical resection as both a diagnostic and a
therapeutic maneuver. Others, such as those with extremely
poor performance status or those suspected of widely metastatic disease, may undergo no testing at all. The next sections present a discussion of the attributes of each of the
staging options available, divided into noninvasive and
invasive techniques.
CHEST RADIOGRAPHY
Many lung cancers are detected initially by plain chest
radiograph. In certain situations, chest radiography may be
sufficient to detect spread to the mediastinum. For example,
the presence of bulky lymphadenopathy in the superior or
contralateral mediastinal areas may be considered adequate
evidence of metastatic disease to preclude further imaging
evaluation of the chest. This may be particularly true if the
patient is too ill or unwilling to undergo treatment of any
kind. Still, most patients should undergo a chest CT scan
unless they are so debilitated that no further evaluation or
treatment is planned. The chest radiograph is simply too
insensitive a measure of mediastinal lymph node involvement with lung cancer and thus further noninvasive or
invasive assessment is usually necessary.
CHEST COMPUTED TOMOGRAPHY
The vast majority of patients who present with lung cancer
will undergo chest CT, which can confirm the suspicion of
lung cancer or raise the suspicion of an alternate diagnosis.
CT is helpful in defining the size, location, and characteristics of the primary mass (e.g., circumscribed, spiculated,
calcified), the presence or absence of lymphadenopathy,
and, if performed through the adrenal glands, the presence
of abnormalities in the liver and adrenal glands. The bony
structures of the thoracic cavity can also be evaluated by
chest CT.
Chest CT is the most widely available and commonly used
noninvasive modality for evaluation of the mediastinum in
lung cancer. Numerous studies of CT have been performed
comparing clinical staging by CT with the “gold standards”
of mediastinoscopy or surgery. The results demonstrated
that, regardless of the lymph node size used as a threshold
for defining malignant adenopathy, CT findings in isolation
could not be considered as conclusive evidence that lymph
nodes were malignant. In other words, in all studies, there
are meaningful numbers of false-positive cases detected by
CT (see eFigs. 53-1 and 53-2). The vast majority of reports
evaluating the accuracy of CT for mediastinal lymph node
staging have employed the administration of intravenous
contrast material. Although contrast is not absolutely necessary in performing chest CT for this indication, it is helpful
to distinguish vascular structures from lymph nodes as well
as to delineate mediastinal invasion from centrally located
tumors. The most widely accepted criterion for an abnormal
lymph node on CT is a lymph node with a diameter of 1 cm
or greater across the short axis.
The American College of Chest Physicians (ACCP) compiled
the studies assessing the performance characteristics of CT
for staging the mediastinum in a meta-analytic format.38
Thirty-five studies were identified, comprising 5111 evaluable patients. The pooled sensitivity of CT for staging the
mediastinum was 51% (95% CI, 47% to 54%) and the
pooled specificity was 86% (95% CI, 84% to 88%). The corresponding positive and negative likelihood ratios were 3.4
and 0.6, respectively, confirming that CT has a limited
ability to either confirm or exclude mediastinal metastasis.38 However, because CT guides the selection of nodes for
biopsy by mediastinoscopy or transbronchial, transthoracic, or transesophageal needle aspiration, it remains an
important diagnostic tool in lung cancer. The limitation of
CT-based mediastinal lymph node evaluation is evident in
that 5% to 15% of patients with clinical T1N0 lesions will
be found to have positive lymph node involvement by surgical lymph node sampling (eFig. 53-3).39 Perhaps the most
important message in evaluating the accuracy of CT is that
approximately 40% of all nodes deemed malignant by CT
criteria are actually benign (see eFigs. 53-1 and 53-2),
depending on the patient population.40 Specificity can be
affected by clinical factors such as the presence of obstructive pneumonitis.40 There is no node size that can reliably
determine stage and operability. When CT criteria for identification of a metastatic node are met, the clinician must
still prove beyond reasonable doubt by biopsy or resection
that the node is indeed malignant. Given the limitations of
the imperfect sensitivity and specificity of CT, it is usually
inappropriate to rely solely on CT to determine mediastinal
lymph node status. Nonetheless, CT continues to play an
important and necessary role in the evaluation of patients
with either a known or suspected lung cancer who are eligible for treatment.37
CT can also be helpful in the evaluation of pleural effusion in patients with lung cancer. The CT scan can indicate
the presence or absence of fluid, the contour of the pleural
space, and whether or not nodules or masses are present on
the pleural surface (eFig. 53-4A and B). However, the clinician should interpret these findings with caution because
pleural disease can predate cancer and the presence of
pleural effusion does not guarantee that the cytology will
be positive. This is an important staging issue because the
finding of malignant pleural effusion in NSCLC is considered evidence of metastatic disease (stage IV). If the pleural
fluid has benign cytology (e.g., it represents fluid from
obstructive pneumonia), then the patient may still be considered for surgical resection. To resolve this issue, recommendations have been made to perform thoracentesis with
cytology on two separate occasions, followed by thoracoscopy to evaluate the pleural surface directly (eFig. 53-5). If
the patient remains cytology-negative, then the patient
should be considered to be at the lower, nonmetastatic stage
and be treated accordingly. Thoracoscopy can be helpful in
differentiating the extent of the primary tumor involvement
into or through the pleura but, at times, open thoracotomy
is needed to sort out this issue. (See Chapters 24 and 82.)
POSITRON EMISSION TOMOGRAPHY
Perhaps the single most notable addition to the staging
armamentarium for the evaluation of lung cancer is PET
(see Chapter 21). Because the image is created by the biologic activity of neoplastic cells, PET is a metabolic imaging
technique based on the function of a tissue rather than on
its anatomy. Lung cancer cells demonstrate increased cellular uptake of glucose and a higher rate of glycolysis when
compared with normal cells.41 The radiolabeled glucose
analogue 18F-fluorodeoxyglucose (FDG) undergoes the same
cellular uptake as glucose but, after phosphorylation, is
not further metabolized and becomes trapped in cells.42
Accumulation of the isotope can then be identified using a
PET detector. Specific criteria for an abnormal PET scan are
either a standard uptake value of greater than 2.5 or uptake
in the lesion that is greater than the background activity of
the mediastinum (see eFig. 53-1B and C, eFig. 53-3B, E, and
F, and Fig. 21-1F-J). It has proved useful in differentiating
neoplastic from normal tissues. In two well-performed
studies that evaluated the use of PET in the preoperative
setting for lung cancer,43,44 nearly 20% of patients were
staged differently after evaluation by PET (see eFigs. 53-1,
53-2, and 53-3, and Fig. 21-3), However, the technique is
not infallible because certain nonneoplastic processes,
including granulomatous (eFig. 53-6) and other inflammatory diseases and infections may also demonstrate positive
PET imaging. Furthermore, size limitations are also an
issue, with the lower limit of resolution of the study being
approximately 7 to 8 mm depending on the intensity of
uptake of the isotope in the abnormal cells (eFig. 53-7AD).43 One should not rely on a negative PET finding for
lesions less than 1 cm on CT.
A burgeoning number of studies in the last several years
have reported on the utility of PET in the assessment of the
mediastinum in patients with lung cancer. Increasing availability of the technology now allows PET to be used widely
as a diagnostic tool. PET is primarily a metabolic examination and has limited anatomic resolution. It is possible for
PET to identify lymph node stations but not individual
lymph nodes. CT provides much more anatomic detail but
lacks the functional information provided by PET. The third
edition of the ACCP guidelines on lung cancer reviewed the
complexity surrounding PET.37 While PET provides information about the primary tumor, mediastinal lymph nodes,
and sites of distant metastasis, the contribution that it
makes to the stage evaluation is influenced by a multitude
of factors. These include the probability of cancer, likelihood of metastasis, and the extent that the investigation for
metastases has been completed by other modalities.
To date, there have been five randomized controlled trials
to evaluate the role of PET.45-49 The variation in results
among the studies was likely due to the significant differences among the patients involved, the prior evaluations,
and risk for advanced disease. While two of the studies demonstrated a reduction in the number of noncurative resections from 40% to 20%,46,49 another detected no difference
in the number of thoracotomies performed or of sites of
distant metastasis.45 This latter study primarily involved
stage I patients with extensive preenrollment imaging
explaining why there was no difference detected between
the PET and conventional staging arms.
Population-based studies using the U.S. National Cancer
Data Base and the Surveillance, Epidemiology and End
Results registry suggest that the use of PET has had a positive impact on stage migration from stage III to stage IV
classification (eFig. 53-8).50,51 Conversely, PET adds little to
the staging of patients with clinical stage I cancers.50,52 PET
is also of limited value in those with ground-glass opacities
with or without a solid component because these patients
are at low risk for nodal and distant metastatic disease.53
Compared with conventional staging, staging by PET is,
on average, 20% more correct in identifying nodal or distant
metastasis in randomized controlled trials.44-46 Confirmation of PET findings, however, is imperative because, as is
945
946
known for CT, PET can be wrong. PET also carries the
possibility of incorrectly upstaging a patient. Whereas a
negative mediastinal PET may obviate the need for mediastinoscopy before thoracotomy in certain situations, a positive mediastinal PET should not negate further evaluation
or the possibility of resection. In the latter case, lymph node
sampling should still be pursued because the possibility of
a false-positive PET scan cannot be ignored.
Where PET is available, a PET scan should be obtained
during the staging evaluation for lung cancer.54 Newer
technology includes CT-PET fusion, a single machine that
incorporates CT and PET during the same scan. This allows
the clinician to obtain anatomic (CT) and functional (PET)
images simultaneously. Studies suggest an improvement in
the number of patients correctly staged with this modality
over CT or PET alone.55,56 The future of PET in lung cancer
may also include its use to evaluate response to treatment.
Due to potential false positive images, the optimal timing for
PET following treatments will require further evaluation,
especially when chest radiotherapy is used. For example, it
may be more useful later in the post-stereotactic body radiation therapy (SBRT) period (i.e., after the first year) rather
than early in the period (i.e., within the first 3 to 6
months).56a
MAGNETIC RESONANCE IMAGING
There are very few circumstances in which magnetic resonance imaging (MRI) is a useful tool in staging lung cancer.
However, MRI can be useful in evaluating superior sulcus
tumors, especially for possible invasion of the brachial
plexus, and for evaluating vertebral invasion.
SEARCH FOR METASTATIC DISEASE
The purpose of extrathoracic scanning in NSCLC is usually
to detect metastatic disease at common metastatic sites,
such as the adrenal glands, liver, brain, and skeletal system,
thereby sparing the patient fruitless surgical intervention.57
CT of the chest (eFig. 53-9A), CT (eFig. 53-9C) or MRI with
contrast of the brain, and 99mTc nuclear imaging of the skeletal system are the conventional staging studies when the
clinician needs to evaluate for metastatic disease. The use
of whole-body PET and PET-CT (see eFig. 53-8) for extrathoracic staging has advanced the field of metastatic disease
evaluation. Studies demonstrate that PET and PET-CT outperform conventional staging tests in the evaluation of
metastatic disease to key specific distant sites including
adrenal glands, liver, and bone (see eFig. 53-8). PET reveals
unsuspected metastases in 6% to 37% 58-61 (see eFig. 53-8
and Fig. 21-4). This allows for more accurate TNM staging,62
stage shift,50,63 and changes in management including
more appropriate consideration of surgical candidacy.62,64,65
Detection of brain metastases is a problem for PET because
the high background brain FDG uptake can mask the small
size of most brain metastases, which can be either hypermetabolic or hypometabolic.66 There is some evidence to
suggest that integrated PET-CT has an accuracy that nears
diagnostic brain CT (see eFig. 53-8B).67
The initial clinical evaluation may reveal abnormalities,
such as abnormal symptoms, physical findings, and routine
blood tests, that then lead to an expanded clinical evaluation
Table 53-4
Expanded Clinical Evaluation
SYMPTOMS ELICITED IN HISTORY
Constitutional—weight loss >10 lb (>4.5 kg)
Musculoskeletal—focal skeletal pain
Neurologic—headaches, syncope, seizures, extremity weakness,
recent change in mental status
SIGNS FOUND ON PHYSICAL EXAMINATION
Lymphadenopathy (>1 cm)
Hoarseness, superior vena cava syndrome
Bone tenderness
Hepatomegaly (>13-cm span)
Focal neurologic signs, papilledema
Soft tissue mass
ROUTINE LABORATORY TESTS
Hematocrit < 40% in males
Hematocrit < 35% in females
Elevated alkaline phosphatase, GGT, AST, calcium
AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase.
(Table 53-4).57 If a patient has abnormalities on these clinical evaluations, scans will be abnormal in around 50% of
cases. The third iteration of the ACCP guidelines for NSCLC
staging recommends PET to evaluate for metastasis (except
for metastasis to the brain) for patients with a normal clinical evaluation and no suspicious extrathoracic abnormalities on chest CT being considered for curative-intent
treatment.37 Advanced thoracic lesions and mediastinal
lymphadenopathy are important variables because these
are associated with more scan abnormalities.57,68 This is
particularly true for N2 disease, in which asymptomatic
metastases have been documented at a higher rate than
would have been expected (see eFig. 53-8).68 Although
several studies have documented a higher incidence of
brain metastases in patients with adenocarcinomas than in
those with squamous cell cancers,69,70 the largest single
series of patients with stage I and II lung cancer found no
difference.71
Several important caveats must be considered in the
search for metastatic disease. First and foremost, there is the
problem of false-positive scans. Adrenal adenomas (present
in 2% to 9% of the general population), hepatic cysts,
degenerative joint disease, old fractures, and a variety of
nonmetastatic space-occupying brain lesions are present in
the general population. When clinically indicated, additional imaging studies, biopsies, or both are performed to
establish the diagnosis; however, complications and costs
resulting from such subsequent investigations have received
less attention.72 There is also the problem of false-negative
scans, scans that fail to detect actual metastases. For
example, in a CT study of the adrenal glands, Pagani73
found metastatic NSCLC by percutaneous biopsy in 12%
of radiologically normal adrenal glands. An additional
problem is that the studies in this area often fail to specify
exactly which elements make up the prescan clinical evaluation or that the studies use differing clinical indicators. For
example, organ-specific findings such as headache and
non–organ-specific complaints such as weight loss are both
important.74,75 In addition, in many studies, abnormal findings on scans have not been pursued with biopsies to prove
metastatic disease. Finally, there are few prospective randomized trials and outcome studies to guide appropriate use
and interpretation of extrathoracic scanning. It is hoped
that careful studies will improve the workup of patients
with lung cancer.
Adrenal and Hepatic Imaging
It is relatively common to encounter adrenal masses on
routine CT, but many of these lesions are probably unrelated to the malignant process. A unilateral adrenal mass
in a patient with NSCLC is more likely to be a metastasis
than a benign lesion according to some studies,76,77 but not
others.78,79 In the setting of clinical T1N0 NSCLC, adenomas predominate,80,81 whereas in the setting of large intrathoracic tumors or other extrathoracic metastases, adrenal
metastases are more common.77,82 Many studies suggest
that the size of a unilateral adrenal abnormality on CT is
an important predictor of metastatic spread, but this is not
a universal finding.83 Lesions larger than 3 cm are more
likely to signify metastases (see eFig. 53-9A), but benign
disease is still possible.
For adrenal masses, CT, MRI, PET, percutaneous biopsy,
and even adrenalectomy can be used to help distinguish
benign from malignant disease. Well-defined, lowattenuation (fatty) lesions with a smooth rim on unenhanced CT are more likely to be benign adenomas,84-86 but
the CT appearance of many lesions is insufficiently distinctive.84 Follow-up scanning with repeat CT, serial ultrasonography, MRI (especially with chemical shift and dynamic
gadolinium-enhanced techniques87), or 6-β-iodo-131Imethyl-norcholesterol scanning88 can sometimes help with
the critical distinction between metastatic disease and
adenoma. One study demonstrated the utility of PET-CT in
differentiating between benign and metastatic malignant
adrenal masses in patients with lung cancer.89 In 110
adrenal masses ranging in size from 0.5 to 6.3 cm, the sensitivity, specificity, and accuracy for detecting metastatic
disease were 97% (74 of 76), 94% (31 of 34), and 95%
(105 of 110), respectively (eFig. 53-10). The positive predictive value was 95% (74 of 77), and the negative predictive value was 94% (31 of 33).
Percutaneous adrenal biopsy is a relatively safe and effective means of achieving a definitive diagnosis in doubtful
cases and is especially important when the histology of the
adrenal mass will dictate subsequent management.90,91
However, this procedure may be nondiagnostic or infeasible
due to anatomic constraints. When insufficient material
results from a biopsy, repeat aspiration or even adrenalectomy should be considered.83,84
Most liver lesions are benign cysts and hemangiomas, but
CT with intravenous contrast (or ultrasound) is often
required to establish a likely diagnosis.39 Percutaneous
biopsy can be performed when diagnostic certainty is
required. PET can detect liver metastases with a diagnostic
accuracy ranging from 92% to 100% (eFig. 53-11) with
rare false-positive results; however, the data in NSCLC are
currently limited.92-94
Brain Imaging
In most studies, the yield of CT/MRI of the brain in NSCLC
patients with negative clinical examinations is 0% to
10%,57,95-100 possibly rendering the test cost-ineffective.101
The negative predictive value of the clinical evaluation in
this setting is 95% (range, 91% to 96%).
An association of positive findings between brain metastases and N2 disease in the chest and adenocarcinoma has
been described.70,97,99 The false-negative rate, wherein
patients return with brain metastases within 12 months of
the original scan, is reported to be 3%.99 False-positive scans
can be a problem in up to 11% of cases due to brain
abscesses, gliomas, and other lesions102; therefore biopsy
may be essential in cases in which management is critically
dependent on the histology of the brain lesion.
MRI is more sensitive than CT of the brain and picks
up more lesions and smaller lesions103 but, in some studies,
this has not translated into a clinically meaningful difference in terms of survival.104 Although studies show that
MRI can identify additional brain lesions in a particular
patient, there are no studies that show that MRI is better
than CT in its ability to identify additional patients with
brain metastases from lung cancer. Therefore CT is an
acceptable modality for evaluating patients for metastatic
disease.37 However, MRI remains the preferred modality at
many centers.
Bone Imaging
False-positive abnormalities in radionuclide bone scintigraphy are common concerns because of the frequency of
degenerative and traumatic skeletal damage and the difficulty in obtaining a definitive diagnosis via follow-up
imaging or biopsy. With a negative clinical assessment, the
negative predictive value for radionuclide bone imaging is
90%. PET has excellent performance characteristics for
determining bone metastases (eFig. 53-12) with a specificity, sensitivity, negative predictive value, and positive predictive value all greater than 90%.94,105 The accuracy of PET
was superior to radionuclide bone scanning in direct comparison studies.106-108
SUMMARY
The noninvasive clinical staging of lung cancer relies on the
clinical evaluation and a number of readily available staging
studies. The clinician must be wary of abnormal scans that
may falsely suggest metastatic disease to the mediastinum
and distant sites. Tissue confirmation by whatever means
necessary is the rule rather than the exception before deciding on correct stage and the most appropriate treatment. If
the patient has clinical findings indicative of metastatic
disease, further evaluation is necessary because nearly 50%
of the time the patient will have metastases. Even if the
clinical evaluation is normal and imaging does not demonstrate suspicious extrathoracic abnormalities, PET imaging
should be done where available in those being considered
for curative-intent treatment.37
INVASIVE DIAGNOSTIC AND
STAGING TECHNIQUES
There are a myriad of methods that can be used to diagnose and stage patients with lung cancer. In certain circumstances, this is accomplished with a single test. For
example, a positive percutaneous biopsy (or endoscopic
ultrasound-guided fine-needle aspiration) of the adrenal
947
948
gland performed as a first test in a patient with a lung mass
will provide both a diagnosis and a stage (stage IV) simultaneously. Every effort should be made to use the least
invasive, most accurate procedure to expedite the patient’s
treatment, to minimize patient discomfort and inconvenience, and to ensure that the most appropriate treatment
is rendered.
SPUTUM CYTOLOGY
Sputum cytology is the least invasive method for obtaining
a diagnosis of lung cancer. Its accuracy depends on the
expertise of the health care team in obtaining the sample
(three samples are required), the preservation technique,
and the size and location of the lesion. Central lesions are
more likely to yield positive cytologic results than are
peripheral lesions.109 Sputum cytology should be obtained
in all patients with central lesions who are at risk for more
invasive biopsy techniques and considered in those with
hemoptysis with or without a mass on chest radiography.
Previously published systematic reviews have summarized
the performance characteristics for sputum cytology for the
diagnosis of suspected lung cancer.109,110 The ranges for
sensitivity and specificity were 42% to 97% and 68% to
100%, respectively. The accuracy of sputum cytology is
highly variable, so, in patients suspected of having lung
cancer with negative sputum cytology, further testing
should be performed.53
TRANSTHORACIC NEEDLE ASPIRATION
Transthoracic needle aspiration (TTNA), usually under ultrasound (see Fig. 19-3), CT, or fluoroscopic guidance, is an
expedient and relatively safe way to diagnose the primary
tumor mass and establish a diagnosis of lung cancer (see
Figs. 19-1 and 19-6). As a general rule, if a lesion is less
than 3 cm in size and lateral to the mid-clavicular line
(eFig. 53-13), TTNA should be considered if tissue diagnosis is necessary. One important point about TTNA or other
nonsurgical biopsy techniques for peripheral pulmonary
lesions is that they afford no preoperative benefit because
they do not eliminate the need for surgery in most cases.111
For a patient presenting with a solitary pulmonary nodule
suspicious for malignancy (e.g., noncalcified, upper lobe,
spiculated lesion in a long-term smoker), the diagnosis,
stage, and therapy can be accomplished simultaneously
with a thoracotomy and surgical resection. Thus TTNA
may be essential only in certain situations: patients who
are poor surgical candidates but who require tissue diagnosis prior to treatment, patients in whom a noncancerous
lesion is strongly suspected (see Fig. 19-7), patients who
request that a diagnosis of cancer be confirmed before
considering surgery, and patients with high likelihood of
metastatic disease (see Fig. 19-2). The sensitivity and specificity of TTNA are 90% and 97%, respectively109 (see
Chapter 19).
One drawback of TTNA is the risk of pneumothorax.
Several investigations have reported a 15% to 45% risk of
pneumothorax for CT-guided TTNA.17,112-114 Although
pneumothorax may lead to hemodynamic compromise
without therapeutic tube thoracostomy, in most cases of
pneumothorax secondary to TTNA, treatment is not
required.115 The primary factors shown to increase the risk
or incidence of pneumothorax are the presence of emphysema, a smaller lesion size, and a greater depth of needle
penetration from the pleural surface to the edge of the lesion.
FIBEROPTIC BRONCHOSCOPY
More than 50% of patients with advanced-stage lung
cancer will have involvement of the central airways either
by bulky endobronchial disease, extension into the airways,
or extrinsic compression of the airways by the tumor or by
lymphadenopathy.116 Patients with known or suspected
lung cancer may have symptoms due to endobronchial
involvement that require airway inspection with bronchoscopy: shortness of breath, unilateral wheezing, hemoptysis, and cough. Endobronchial lesions can be visualized
easily and biopsied through a flexible bronchoscope. The
yield with three or more biopsies should approach 100% for
centrally located lesions.117,118 Data from 4507 patients
revealed that central endobronchial biopsies provide the
highest sensitivity (74%), followed by brushings (61%) and
washings (47%).109 The combination provides a diagnosis
in 88% of cases.109 Endobronchial needle aspiration may be
helpful especially when a rim of necrotic debris surrounds
an endobronchial malignancy, because deeper tissue penetration may access viable tumor cells. The addition of
endobronchial needle aspiration to forceps biopsies and
brushings may improve sensitivity to 95% for the diagnosis
of endobronchial cancer.119,120
Submucosal and Peribronchial Lesions
When lung cancer presents with submucosal infiltration
or extrinsic compression from peribronchial disease,
endobronchial forceps biopsy has a lower yield (55%)
than transbronchial needle aspiration (TBNA) (71%).121 In
these situations, normal mucosal markings are often
obscured and the surface is replaced with bronchial collateral vessels and firmer surface tissue, which may have to
be penetrated to reach malignant cells. In addition, peribronchial tumor may be inaccessible to biopsy forceps.
TBNA can be more effective if the lesion is close enough
to the tracheobronchial tree to be encountered with a 1.3to 1.5-cm-long needle. Of note, in cases like this when
sampling error may be high, diagnostic yields may be
improved by combining different methods or by using
with endobronchial ultrasound (EBUS)-TBNA, which offers
the advantages of real-time ultrasound and an adjustable
needle length up to 4 cm.
Navigational Bronchoscopy
Navigational bronchoscopy provides a novel option for the
diagnosis of peripheral lung lesions (see Chapter 22). It has
a lower pneumothorax risk than TTNA and a higher diagnostic yield for peripheral lesions than traditional bronchoscopy.122 In general, there are three types of navigational
bronchoscopy: (1) radial probe endobronchial ultrasonography, which is conventional radial EBUS using guide
sheaths that allow the use of biopsy tools after successful
navigation to the target; (2) virtual bronchoscopy, which
creates a CT-based “road map” overlaid on endoscopic realtime images; and (3) electromagnetic navigational bronchoscopy which uses a virtual navigation system with
steerable devices.123 A combination of navigational techniques has been shown to augment the diagnostic yield
(88%) when compared to either radial probe endobronchial
ultrasonography or electromagnetic navigational bronchoscopy alone.124 A meta-analysis reported the accuracy
and side effect profile of all available guided bronchoscopy
procedures. In 39 studies, which together included more
than 3000 patients, the pooled diagnostic yield was approximately 70% (with wide variation) and the pneumothorax
rate was less than 2% (need for chest tube insertion less
than 1%).125 In addition, navigation may be used for
placement of fiducial markers for stereotactic radiation
treatments.126
Bronchoscopy for Staging Lung Cancer
Initially, the role of bronchoscopy in staging lung cancer
was limited to the determination of T (tumor) status. Now
bronchoscopy has a crucial role in determining the presence of metastatic deposits of tumor in mediastinal lymph
nodes, thus contributing to an accurate and a minimally
invasive staging method for lung cancer.
The use of traditional TBNA in staging lung cancer has
been reported to be both sensitive and specific in diagnosing spread of cancer to lymph nodes.127-129 The overall sensitivity of TBNA for NSCLC is 78% and the specificity is
99%.130 The standard method of performing TBNA starts
with a CT scan of the chest to guide needle aspirations
toward the most involved group of lymph nodes. Lesions
localized by CT can be accessed with bronchoscopy by
measuring the number of CT slices above or below the
carina (or other airway landmarks) and placing the needle
the required distance above or below the landmark corresponding to that number of CT slices. When performing
TBNA, the question invariably arises about the number of
negative passes to perform before stopping. For various
reasons, such as patient comfort and safety, need for sedation, and time spent by medical staff, it is imperative to
manage the time for bronchoscopy. It has been shown that
a plateau in yield for malignancy is achieved after seven
passes with the needle through a lymph node.131 The
importance of having a qualified and experienced cytopathologist on site cannot be overemphasized. Thorough
interpretation by such individuals who are available for
rapid on-site evaluation has been shown to enhance yield
from TBNA.132 With the assistance of these individuals, the
adequacy of sampling can be rigorously assessed. All
samples should contain a preponderance of lymphocytes
to define true nodal sampling. Specimens without lymphocytes should be deemed unsatisfactory, and the presence
of respiratory epithelium should raise concerns about
contamination.
TBNA allows for minimally invasive sampling of the
mediastinum and hilar lymph nodes and potentially avoids
more invasive procedures such as mediastinoscopy, mediastinotomy, and open thoracotomy. There is no doubt that the
combined use of TBNA and CT can improve not only the
diagnostic but also the staging evaluation of lung cancer.
However, thus far, there has been wide variability in training and in usage of this helpful procedure. It is also operatordependent, with certain techniques allowing for higher
yields. See Chapter 22 for an in-depth discussion of
bronchoscopy.
ENDOSCOPIC ULTRASOUND
Endoscopic ultrasound (EUS) is another modality that has
significantly impacted lung cancer staging, primarily due to
its superior ability to sample the posterior mediastinum
through the esophageal wall. Currently, EUS with fineneedle aspiration is performed using real-time ultrasound.
In pooled analysis of 2433 patients with lung cancer
and mediastinal adenopathy, EUS had a sensitivity and
specificity of 89% and 100%, respectively.37,130,133-156 In
patients with lung cancer who have no adenopathy seen on
CT, EUS has been shown to sample nodes as small as 3 mm
in diameter. This is useful given the high incidence of metastasis found in normal-sized lymph nodes in lung cancer.157
Based on surgical studies, it may be possible to predict the
location of mediastinal lymph node metastases at certain
levels based on the location of the tumor. This relationship
may influence the use of EUS in certain patients without
adenopathy on chest CT. Lymphatic pathways favor spread
to aortopulmonary window nodes from left upper lobe
tumors and to subcarinal nodes from left and right lower
lobe lesions.158 EUS has been studied in patients with known
lung cancer without enlarged mediastinal lymph nodes on
CT, and it has detected mediastinal involvement (stage III or
IV disease) in up to 42% of cases.159
In addition, EUS has the advantage of being able to stage
lung cancer from locations outside the mediastinum. The
left lobe of the liver, a substantial part of the right lobe of
the liver, and the left (but not the right) adrenal gland can
be identified and sampled in 97% of patients.160 In addition,
left pleural effusions can be visualized and sampled during
an EUS procedure. EUS is increasingly being combined with
EBUS for minimally invasive staging of lung cancer.161
ENDOBRONCHIAL ULTRASOUND
Perhaps the greatest addition in the armamentarium for
staging lung cancer is endobronchial ultrasound with
transbronchial needle aspiration (EBUS-TBNA). EBUS-TBNA is
indicated for the assessment of mediastinal and hilar lymph
nodes and diagnosis of lung and mediastinal tumors. It can
be used to sample the highest mediastinal (station 1), the
upper paratracheal (station 2R, 2L), the lower paratracheal
(station 4R, 4L), the subcarinal (station 7), as well as the
hilar (station 10) and the interlobar (station 11) lymph
nodes (Fig. 53-1A). The para-aortic (station 6), aortopulmonary window or subaortic (station 5), paraesophageal
(station 8), and pulmonary ligament (station 9) lymph node
stations are usually not accessible by this technique (see Fig.
53-1B). Pooled analysis of 2756 patients shows that EBUSTBNA has a sensitivity and specificity of 89% and 100%,
respectively.37 If a patient presents with a lung mass and
mediastinal lymphadenopathy in accessible lymph node
stations, EBUS-TBNA should be considered as the test of
first choice because this modality can provide a diagnosis
and stage simultaneously. In addition, the role of EBUS in
lung cancer has expanded to include preoperative mediastinal staging and tissue acquisition for molecular analysis
in addition to immunohistochemical staining.162-164
The combination of EUS and EBUS has shown better yield
than either technique alone. A pooled analysis from 7
studies and 811 patients showed a sensitivity and specificity
949
950
of 91% and 100%, respectively.37,135,139,140,165-168 These complementary procedures provide near-complete access to the
mediastinum for staging,135 even in the radiologically
normal mediastinum.140 Among patients with (suspected)
NSCLC, a staging strategy combining endosonography and
mediastinoscopy compared with mediastinoscopy alone
was shown to have greater sensitivity for mediastinal nodal
metastases and led to fewer unnecessary thoracotomies.165
For further discussion of EBUS, see Chapter 22.
thoracotomy despite a negative needle technique. Mediastinoscopy is most often used to sample nodes of the paratracheal (station 4), and anterior subcarinal (station 7) region
(see Fig. 53-1A). Because the subcarinal area is more difficult to sample, mediastinoscopy has a lower yield for lymph
nodes in this area. An extended cervical mediastinoscopy
can be carried out to reach aortopulmonary and paraaortic lymph nodes (stations 5 and 6) by using the same
cervical incision as mediastinoscopy but dissecting into a
different fascial plane. Alternatively, an anterior mediastinotomy (the so-called Chamberlain procedure) may be
needed to sample lymph nodes in these aortopulmonary
and para-aortic locations (stations 5 and 6) (see Fig.
53-1B). Overall, mediastinoscopy has a reported sensitivity
of 78%, with a specificity of 100%.130 Mediastinoscopy
may also differentiate between stage IIIA and IIIB mediastinal involvement, which may be important for prognosis
and potential therapy. As with any surgical procedure,
mediastinoscopy has risks and limitations. It requires
general anesthesia, with a morbidity of 2% and a mortality
of 0.08%.130
MEDIASTINOSCOPY
Mediastinoscopy is the historical gold standard for invasively staging the mediastinum in patients with known or
suspected lung cancer; however, if local expertise is available, ultrasound-guided needle techniques (EBUS-TBNA,
EUS, or their combination) are now recommended as the
best first tests. If there is mediastinal lymph node enlargement regardless of FDG uptake on PET or if there is FDG
uptake in a lymph mediastinal node regardless of its size, a
surgical mediastinal procedure should be performed before
Brachiocephalic
(innominate) a.
Superior mediastinal nodes
1 Highest mediastinal
2 Upper paratracheal
3 Pre-vascular and retrotracheal
4 Lower paratracheal
(including azygos nodes)
1
2R
Aortic nodes
5 Subaortic (A-P window)
6 Para-aortic (ascending
aorta or phrenic)
Ao
4R
Azygos v.
Inferior mediastinal nodes
7 Subcarinal
8 Paraesophageal
(below carina)
9 Pulmonary ligament
N2 nodes (1-9) ipsilateral
N3 nodes (1-9) contralateral or supraclavicular
or scalene nodes
4L
10R
PA
7
11R
11L
8
12R, 13R, 14R
A
10L
9
10 Hilar
11 Interlobar
12 Lobar
13 Segmental
14 Subsegmental
12L, 13L, 14L
Inf. pulm. ligt.
Figure 53-1 Mediastinal lymph node maps. A and B, the 14 stations for lymph nodes used in lung cancer staging are shown in association with anatomic
landmarks. The N2 nodes are within the mediastinal pleural envelope (1-9) and the N1 nodes are outside the mediastinal pleural envelope, in the hilar
(10) or intrapulmonary (11-14) locations. a, artery; Ao, aorta; A-P, aortic-pulmonary; PA, pulmonary artery; v, vein. (Redrawn from Mountain CF, Dresler CM:
Regional lymph node classification for lung cancer staging. Chest 111:1719, 1997.)
3
Ligamentum
arteriosum
L. pulmonary a.
Phrenic n.
6
Superior mediastinal nodes
1 Highest mediastinal
2 Upper paratracheal
3 Pre-vascular and retrotracheal
4 Lower paratracheal
(including azygos nodes)
Aortic nodes
5 Subaortic (A-P window)
6 Para-aortic (ascending
aorta or phrenic)
Inferior mediastinal nodes
7 Subcarinal
8 Paraesophageal
(below carina)
9 Pulmonary ligament
N3 nodes (1-9) contralateral or supraclavicular
or scalene nodes
Ao
5
PA
10 Hilar
11 Interlobar
12 Lobar
13 Segmental
14 Subsegmental
B
Figure 53-1, cont’d.
TREATMENT OF LUNG CANCER
The overall 5-year survival for patients diagnosed with lung
cancer is a dismal 14%.169 This figure has not changed substantially since the 1980s. The survival curves vary by
stage, with earlier stage lung cancer patients enjoying a
much better survival than patients with later stage disease.
Treatment is based on the stage of the disease and the
patients’ performance status at the time therapy is initiated.
In general, early stage disease is surgically managed, locally
advanced disease is managed with chemotherapy and
radiotherapy, and advanced disease is managed with chemotherapy with supportive care or supportive care alone.
This paradigm has shifted toward more multimodality
therapy (surgery, chemotherapy, and radiotherapy).170-173
This raises the issue of how best to manage patients with
newly diagnosed lung cancer through their diagnosis,
staging, and therapy. The ACCP guidelines on lung cancer
recommend the use of a multidisciplinary lung cancer
setting wherein patients can be evaluated by the major disciplines involved in the care of these patients, namely the
pulmonologist, the thoracic surgeon, and the medical and
radiation oncologists.174 A “tumor board” that includes the
aforementioned specialties, with the addition of chest radiology, pathology, nursing, and social work, should review
all new cases to ensure that patients receive optimal treatment and are considered for enrollment in clinical trials.
In addition to surgery, treatment such as chemotherapy
and or radiotherapy can be applied in a neoadjuvant or
adjuvant fashion. Neoadjuvant therapy indicates therapy
given before the main treatment; it has the potential to
reduce tumor volume, treat micrometastases, and improve
outcomes. Adjuvant therapy is therapy given after the main
treatment; it is aimed at treating any residual tumor or
micrometastases with the aim of preventing tumor recurrence. The efficacy of treatments can be assessed by median
survival time (MST) or by progression-free survival (PFS), the
length of time a patient lives with lung cancer before it
progresses.
PROGNOSTIC FACTORS FOR LUNG CANCER
Based on an analysis of large databases of inoperable lung
cancer cases, the strongest predictors of survival are good
performance score (Karnofsky scale), lower extent of disease
(stage), age, and absence of weight loss.175-177 Some reports
have shown female gender to be a predictor of better survival, but this varies between studies. Performance score
and the presence or absence of symptoms are predictors of
outcome even with resectable early-stage disease.178-180 For
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Table 53-5
Summary of Current Treatment Strategies for Non–Small Cell Lung Cancer
Stage
Surgery
Chemotherapy
Radiotherapy
Chemoradiotherapy
Comments
I and II
1st line
Adjuvant—stage IIA, IIB
2nd line
No
Survival improvement with adjuvant
therapy (= 5%)
Radiotherapy for inoperable patients
IIB (T3N0M0)
Pancoast
1st line
No
No
1st line—neoadjuvant
Neoadjuvant chemoradiotherapy improves
survival in this subset of stage IIB
IIIA
1st line
Adjuvant treatment—in
totally resected IIIA
Controversial
1st line
IIIB Unresectable
No
No
No
1st line
Combined chemoradiotherapy followed by
surgery is feasible, but more data are
needed to recommend routinely
Treatment similar to unresectable stage IIIA
IV
No
1st line*
No
No
Radiotherapy is used for palliation only
All stage IV should have mutational analysis,
including EGFR, EML4-ALK, and KRAS.
Bevacizumab is approved as an adjunct to chemotherapy in the first-line setting in patients with nonsquamous histology and no other contraindications.
*The targeted therapies are indicated as first-line treatment for those with advanced NSCLC and documented EGFR mutations or EML4-ALK fusion. Erlotinib is
FDA-approved as first-line treatment of metastatic NSCLC for patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution
mutations.
EGFR, epidermal growth factor receptor; FDA, U.S. Food and Drug Administration; NSCLC, non–small cell lung cancer.
example, in stage I NSCLC patients undergoing curative
resection, those who were symptomatic at presentation had
worse survival than those who were asymptomatic.179
Although individual reports have noted superior survival
for patients with one cell type of NSCLC versus another, the
general consensus in the literature is that histologic subtypes of NSCLC are not a major predictor of survival.178,179,181
Absence of smoking or smoking cessation has been associated with improved survival. The maximal standard uptake
value of the primary tumor on PET has been inversely correlated with survival.182
In more recent years, there have been numerous reports
that various molecular markers are associated with
outcome. Some of the best known markers include KRAS,
epithelial growth factor receptor (EGFR), EML4-ALK translocation, p53, p16, and BCL2. However, in many instances,
the results are conflicting about the prognostic significance
of these individual molecular markers,183-185 perhaps due to
the types of cases under review and to individual laboratory
variations in techniques for measuring these molecular
markers. In a meta-analysis, KRAS mutations were associated with poorer survival, especially in adenocarcinoma in
which the hazard ratio was 1.6 (95% CI, 1.3 to 2).186 Testing
the genetic profile of samples obtained from metastatic
lymph nodes or malignant pleural effusions in those patients
with stage III and IV disease has become standard practice,
because this allows for the selection of targeted drug therapies specific for the mutation as first-line chemotherapy.
NON–SMALL CELL LUNG CANCER TREATMENT
BY STAGE
This section presents a discussion of the treatment of
NSCLC by stage and cell type, followed by a discussion of the
treatment of SCLC. Table 53-5 presents an overview of
treatment strategies for NSCLC based on stage.
Stage I
In the most recent staging system for NSCLC, stage I NSCLC
is broken down into stage IA (tumors ≤ 2 cm [T1a] (eFig.
53-14A) and tumors between 2 and 3 cm [T1b]) (see eFig.
53-14B) and stage IB (tumors between 3 and 5 cm [T2a])
(see eFig. 53-15). All stage I tumors are completely surrounded by lung parenchyma greater than 2 cm away from
the carina and do not invade the chest wall or parietal
pleura (Fig. 53-2). Stage I lung cancer does not include
patients who have malignant lymph node disease or patients
with metastatic disease. Thus the TNM classification is
either T1aN0M0, T1bN0M0 (stage IA), or T2aN0M0 (stage
IB). The differences between the two are the size of the
primary tumor and the survival after surgical resection.
Although stage I disease offers the best chance for longterm survival, the sad fact is that only 15% of all lung
cancers present with stage I disease.187,188
The current treatment for stage I lung cancer is surgery
alone. The surgical procedure of choice is a lobectomy or
pneumonectomy with mediastinal lymph node sampling.
It should be recognized that the patient must be a reasonable surgical candidate. The 5-year survival for surgically
resected stage IA lung cancer is 73%, whereas the survival
for stage IB lung cancer is 58%.33 Local postoperative radiation for stage I and II lung cancer, after either complete or
incomplete resection of the tumor, has not been found to
be of any benefit.187 Postoperative adjuvant chemotherapy
has not been shown to improve survival for those with
resected stage I disease.189 A further discussion of postoperative adjuvant therapy is presented later (see “Stage
IIIA”).
Some patients are surgically resectable but medically
inoperable, usually because the patient does not have the
pulmonary reserve to tolerate a lobectomy. These patients,
particularly those with T1 tumors, may be able to tolerate
a wedge resection or segmentectomy of their tumor as
opposed to a lobectomy or pneumonectomy. In such cases,
the local recurrence rate is higher than that of a complete
resection, but the overall 5-year mortality is no different.190
However, for patients with smaller peripheral stage I
lung cancers, anatomic segmentectomy may offer local
control, the opportunity for prolonged disease free survival,
and overall survival that is comparable to lobectomy.190a
Still, whenever possible, a complete anatomic resection
is preferred over a minimal resection. For discussion of
A
B
Figure 53-2 Stage I disease. CT (A) and PET (B) scans of a patient with
T1N0M0 tumor (arrows).
radiofrequency ablation and other nonsurgical treatments,
see Chapter 19.
Patients who are “close calls” for surgery should be thoroughly evaluated by both a pulmonologist and a thoracic
surgeon before making a decision on operability. As previously stated, there is a difference between a patient who is
resectable and a patient who is operable. Chapter 27 is
devoted to the preoperative evaluation of patients with lung
disease, but a brief review is warranted here. Patients with
a postoperative percent predicted forced expiratory volume
in 1 second or diffusion capacity less than 40% will have a
higher morbidity and mortality following lung cancer
surgery. Patients with borderline values preoperatively
should be referred for a differential ventilation-perfusion
scan for a better prediction of postoperative function. When
there is still a question, a cardiopulmonary exercise test can
be obtained. Compared with those with an oxygen consumption greater than 20 mL/kg/min, patients with an
oxygen consumption between 11 and 19 mL/kg/min have
a higher morbidity but no greater mortality and those with
an oxygen consumption less than 10 mL/kg/min have both
a higher predicted morbidity and mortality.191
For patients who either refuse surgery or are deemed
medically unfit for surgery, primary radiotherapy for cure
can be considered. This approach was evaluated in a metaanalysis of 1 randomized and 35 nonrandomized trials.192
The studies were heterogeneous, and the 5-year cancerspecific survival ranged between 13% and 39%. The authors
concluded that, even in patients with severe emphysema,
radiation therapy can be tolerated if careful planning with
three-dimensional conformal techniques is undertaken.
Conformal indicates that the radiation is designed in 3
dimensions to match the shape of the tumor allowing
maximal targeting to the tumor with minimal injury to
adjacent normal tissue.
More recently, stereotactic body radiation therapy has
been introduced as a highly precise and accurate delivery
method of highly conformal and dose-intensive radiation to
small-volume targets. This method is also referred to as stereotactic ablative body radiotherapy and stereotactic radiosurgery. It is a more aggressive dose intensification than
could previously be achieved using conventional radiotherapy methods.193
In the Radiation Therapy Oncology Group trial (ROTG
0236), patients with biopsy proven stage I NSCLC deemed
medically inoperable received stereotactic body radiation
therapy with 60 Gy in three fractions. Primary tumor
control of 98%, regional control of 87%, and overall survival of 56% at 3 years were achieved.194 This study and
others (ROTG 0618) have demonstrated a dose-response
relationship that favors more intensive regimens with biologically equivalent doses of more than 100 Gy consistently
resulting in more than 90% primary tumor control for T1
tumors and overall survival greater than 50%. A metaanalysis demonstrated an overall survival improvement
with stereotactic body radiation therapy compared with
conventionally fractionated radiation therapy.195
Stage II
Stage II NSCLC lung cancer is divided into stage IIA and
stage IIB. Stage IIA is defined as a T1a-T2aN1M0 and
T2bN0M0 disease and stage IIB includes T2bN1M0
and T3N0M0. The 5-year survivals for stage IIA and IIB are
46% and 36%, respectively.
Stage IIA lung cancer is quite uncommon, representing
between 1% and 5% of patients treated in several surgical
series.196-201 Stage IIB cancer may represent up to 15% of
surgically resected cases.189,196,198,201 For stage IIA and IIB
cancer, surgical therapy is the treatment of choice. There
is no benefit to postoperative radiotherapy. The value of
adjuvant chemotherapy after surgery is discussed later
(see “Stage IIIA”) but, in short, adjuvant chemotherapy is
recommended for all patients with resected stage II disease.
With chest wall invasion (T3N0M0) (eFig. 53-16), an en
bloc resection of the tumor and chest wall is the treatment of choice. A specific discussion of the evaluation
and treatment of Pancoast tumor is discussed later in the
chapter.
The outcome of lung cancer surgery is improved when
the surgery is performed at hospitals with a higher volume
of procedures.197 It is also important that the surgery be
performed by a thoracic surgeon; when lobectomy is
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954
A
B
C
Figure 53-3 Stage IIIA disease. A, CT depicts a primary tumor mass invading the chest wall, resulting in stage IIIA non–small cell lung cancer (NSCLC;
T3N2) (arrow). B, CT depicts enlarged aortopulmonary lymph node (arrow). C, PET with uptake in primary tumor (left image, arrow) and lymph node (right
image, arrow).
performed by a thoracic surgeon compared to a general
surgeon, mortality is nearly halved.202
Stage IIIA
Stage IIIA NSCLC represents a heterogeneous group
of patients with N2 disease (Fig. 53-3) and includes T3N1
patients. In addition, within the new staging system,
patients with T4N0-1 have been down-staged to IIIA from
their previous classification.33,203
For carefully selected T4N0-1M0 patients, surgery may
be indicated with or without neoadjuvant chemotherapy or
neoadjuvant chemoradiotherapy (superior sulcus tumors)
(eFigs. 53-17 and 53-18).204 Individuals with T4N0-1
disease due to main carinal involvement have been treated
with carinal resection with or without pulmonary resection. Carinal resection carries an operative mortality of
10% to 15% and 5-year survival of approximately 20% in
carefully selected series. Patients who are T4N0 solely due
to tumor nodules within the ipsilateral nonprimary lobe
(eFig. 53-19) have a 5-year survival of around 20% with
surgery alone.205
There is substantial debate over what constitutes resectable IIIA (N2) disease. However, there is no debate that
T3N1 disease is best treated with surgical resection. At
surgery, when a complete resection of the lymph nodes and
the primary tumor is possible, some patients are found to
have occult N2 metastasis. If so, these patients are best
served by a resection of all known disease and then by consideration for adjuvant chemotherapy.33,203
It is less certain how best to treat patients when N2
(single or multiple station) metastases are documented
before thoracotomy. The new ACCP guidelines used the
groupings of infiltrative stage III (N2/N3) tumors and
stage III with discrete N2 involvement. In infiltrative stage
III with N2/N3 involvement, the mediastinal nodes can no
longer be clearly distinguished and measured (eFig. 53-20).
These patients have extensive tumor infiltration in the
mediastinum, which partially surrounds the major structures. In patients with infiltrative stage III (N2/N3), good
performance score, and minimal weight loss (≤10%), the
recommended treatment with curative intent is with concurrent chemoradiotherapy.33,203
Two multicenter trials have concluded that concurrent
chemoradiotherapy is superior to sequential therapy
with chemotherapy followed by thoracic radiotherapy.206,207
Concurrent therapy, however, is associated with a higher
rate of severe esophagitis than is sequential therapy. The
recommended chemotherapy is a platinum doublet and the
most common agents are etoposide and cisplatin.208-210
Three cooperative group trials of definitive chemoradiotherapy for unresectable stage III had an MST of 19 to 22
months with 2-year survivals of 40% to 45% and a 5-year
survival of approximately 20%.
For patients with discrete N2 involvement, the ACCP
guidelines recommend that the treatment plan be discussed
by a multidisciplinary team. Either definitive chemoradiotherapy or induction therapy followed by surgery is recommended over either surgery or radiation alone. These
recommendations were largely influenced by the two cooperative group trials that evaluated the role of surgery in
patients with N2 disease.208,211 The European trial randomized patients with histologically proven N2 disease to radiotherapy or surgery after initial induction therapy with three
cycles of a cisplatin doublet chemotherapy.211 The MST was
16 months in the surgery arm and 17 months in the radiotherapy arm.206 The 5-year survival in both arms was 16%
and 14%, respectively, and was not significantly different.
The North American trial also required pathologic proof of
N2 disease and randomized patients to completion radiotherapy or surgery after induction of two cycles of etoposide
and cisplatin with concurrent thoracic radiotherapy of
45 Gy in 25 fractions over 5 weeks.208 The MST was 24 and
22 months in the surgery and radiotherapy arms, respectively, with 5-year survivals of 27% and 20% (hazard ratio
0.87, P=0.24). These survival differences were not statistically significant. However, the PFS favored the surgery arm.
A subset analysis in those having only a lobectomy after
induction therapy did better than a matched group receiving only chemoradiotherapy. This was an unplanned subset
analysis that weakens the strength of this analysis. Accordingly, the role of surgery for stage III with discrete N2
disease has not been definitively answered.
In patients with stage II or IIIA totally resected NSCLC,
adjuvant chemotherapy with four cycles of a cisplatinbased doublet chemotherapy is recommended.203,212 The
Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis
evaluated all stages of totally resected disease and observed
a 5.4% overall 5-year survival benefit with adjuvant chemotherapy. The benefit was the greatest for patients with
stage II and III disease and those with better performance
status. The role of postoperative radiation therapy for
patients with totally resected stage III (N2) remains controversial. Local recurrence varies in reports from 20% to
60%. Some nonrandomized trials suggest possible benefit
from postoperative radiation therapy.213,214 Accordingly, this
option should be discussed with fit patients. A randomized
phase III Adjuvant Radiotherapy (ART) trial is underway to
evaluate postoperative radiation therapy in these patients.
Stage IIIB
Stage IIIB is also a heterogeneous group and includes
T4N2M0 and any T N3M0 patients. There are no phase III
randomized trials to date that demonstrate that neoadjuvant chemoradiotherapy followed by surgery for stage IIIB
disease results in prolonged survival compared with chemoradiotherapy alone.203
Patients with unresectable stage IIIB NSCLC are treated
the same as those with unresectable IIIA disease. The MST
is generally 19 to 22 months, with a 5-year survival of 10%
to 20%. The randomized trials of chemoradiotherapy
included both stage IIIA and IIIB disease participants so it
is not possible to separate out the survival of stage IIIB
patients specifically.209,210 Concurrent chemoradiotherapy
is recommended for both unresectable stage IIIA and IIIB
disease.203 Trials have evaluated multiple daily fractions of
thoracic radiotherapy, but there are no convincing data
that hyperfractionated thoracic radiotherapy (the same
total dose of radiation therapy split into two treatments
in the same day) is superior to standard once-daily
treatment.
Stage IV
Stage IV NSCLC is generally considered to be incurable with
5-year survivals of 1% to 3%. The goal of therapy is to try
to control the disease and palliate symptoms. Major response
rates with current chemotherapy regimens are 10% to
30%. Patients who respond to chemotherapy may gain an
additional 3 to 9 months of life on average but eventually
relapse and die of their disease. In previous trials in the
1970s and 1980s, patients were randomized to best supportive care or systemic chemotherapy. A meta-analysis
evaluated eight of these randomized trials, including more
than 700 patients.215 Each of these trials used a cisplatinbased chemotherapy versus supportive care. With best supportive care, the MST was 4 months and the 1-year survival
was 15%; with chemotherapy, there was an increase in the
MST of 1.5 months and an increase in 1-year survival of
10%. In the 1990s, a number of new chemotherapy agents
were introduced, including paclitaxel, docetaxel, irinotecan, vinorelbine, and gemcitabine. Phase III trials have
incorporated these newer agents in combination with cisplatin or carboplatin.216
Trials comparing single-agent chemotherapy to a chemotherapy doublet containing a platinum compound have
shown that the chemotherapy doublet is superior. Treatment with three drugs has not been shown to be superior
to that with two drugs. Large randomized trials have tried
to identify the optimum chemotherapy doublet.217-219 The
results were uniformly similar, with response rates of 20%
to 30% and MST of 7 to 9 months. No one platinum doublet
has been shown to be superior. The chemotherapy combinations did have different toxicity profiles.
Histology influences response to certain chemotherapeutic agents. A large phase III trial randomized patients to
cisplatin and pemetrexed or gemcitabine and cisplatin.
Whereas there was no difference in the overall survival for
the 847 patients with adenocarcinoma, the survival was
significantly better with the pemetrexed regimen (MST 12.6
months vs. 10.9 months). Conversely, squamous cell
cancers had superior survival with the gemcitabine regimen
(MST 10.8 months vs. 9.4 months).220 The ACCP guidelines
recommend that chemotherapy for stage IV NSCLC should
be guided by histology. Pemetrexed should be limited to
patients with nonsquamous NSCLC.221 In patients with a
good performance score, a platinum-based doublet chemotherapy regimen is recommended.
In the Eastern Oncology Group Trial (E4500), patients
with nonsquamous histology were randomized to treatment with carboplatin and paclitaxel with or without
bevacizumab, a monoclonal antibody that inhibits a vascular endothelial growth factor. Bevacizumab was continued as maintenance therapy after six cycles of therapy in
those responding to treatment or with stable disease.221a
Patients in the bevacizumab arm had a higher response
rate (35% vs. 15%) and better survival (MST 12.3 months
vs. 10.3 months; 2-year survival 44% vs. 15%). A metaanalysis of four randomized trials of NSCLC patients
treated with bevacizumab demonstrated increased PFS and
overall survival in patients treated with combination chemotherapy and bevacizumab than in patients treated with
chemotherapy alone.222 In selected patients with nonsquamous histology and good performance scores, the addition
of bevacizumab is recommended. Hemoptysis, uncontrolled brain metastasis, deep venous thrombosis, and
anticoagulation treatment are contraindications to using
bevacizumab.221
In patients with stable or responding disease whose initial
therapy included bevacizumab, maintenance treatment
with bevacizumab until progression is generally recommended. For patients with an initial platinum-based doublet
chemotherapy and responding or stable disease, maintenance treatment with pemetrexed has been shown to
prolong survival.221 A randomized Eastern Oncology Group
Trial is currently evaluating maintenance treatment with
bevacizumab versus pemetrexed versus the two-drug combination. This is likely to be a definitive study on maintenance therapy.
Targeted Therapy
In 2004, investigators identified activating mutations in the
tyrosine kinase domain of EGFR that predicted response to
novel tyrosine kinase inhibitors (TKIs) in selected patients
with NSCLC223,224 (see Chapter 51). This activating mutation was found to be a “driver” mutation because it was
causal in tumor development; the mutation activated EGFR
signaling thereby driving and sustaining the tumor. Driver
mutations, as opposed to the much more common passenger
mutations, thereby render a tumor vulnerable to blockade
of that single pathway.
Multiple studies have demonstrated that the phenotype
most associated with response to the EGFR-TKIs, gefitinib
and erlotinib, includes adenocarcinoma, never-smoker,
female, and East Asian descent. Subsequent reports have
shown that these are the groups most likely to harbor the
955
956
activating EGFR mutations. Emerging data have demonstrated that KRAS and EGFR mutations are almost always
mutually exclusive and that patients with KRAS mutations
do not respond to EGFR-TKIs.225 Erlotinib has been shown
in a phase III trial in previously treated patients with
NSCLC to result in superior survival versus placebo (6.7 vs.
4.7 months).226 On this basis, erlotinib was approved by
the U.S. Food and Drug Administration (FDA) for second-line
treatment. A phase III trial of gefitinib in second-line
therapy failed to show a significant improvement in survival and approval for second-line therapy was withdrawn
by the FDA in North America.227 In a landmark phase III
trial in East Asia, patients with untreated stage IV disease
were randomized to gefitinib or platinum-based chemotherapy. Of the 437 patient samples tested, 60% were positive for an activating mutation of EGFR. This subgroup
had a significantly better response and PFS after gefitinib
than after chemotherapy. The subgroup negative for
mutations responded better and had a better PFS after
chemotherapy.228
Since that key study of first-line treatment with an EGFRTKI or with chemotherapy, there have been multiple additional trials in patients with EGFR activating mutations. A
meta-analysis of the use of EGFR-TKI in a first-line (13
trials) or in a second-line setting (7 trials) observed a PFS
advantage (HR 0.43) in those patients with an activating
EGFR mutation treated with an EGFR-TKI in the first-line
setting.229 Results were similar when the EGFR-TKI was
used in the second-line setting in those with an activating
EGFR mutation (HR 0.34 for PFS). For patients whose
tumor contains an activating EGFR mutation, the response
rate to an EGFR-TKI is 60% to 80% with a median PFS of
9 to 12 months and an overall survival of approximately 2
years.230 As a result of these and other studies, erlotinib is
FDA-approved as first-line treatment of metastatic NSCLC
for patients whose tumors have EGFR exon 19 deletions or
exon 21 (L858R) substitution mutations.
The anaplastic lymphoma kinase (ALK) fusion gene is the
second most common driver mutation for which there is an
effective TKI. The efficacy of the first generation ALK-TKI,
crizotinib, was demonstrated in a phase I study that was
expanded and resulted in a rapid FDA approval of the drug.
Of 143 patients with stage IV NSCLC with an ALK fusion,
the objective response rate was 61% and a median PFS
was 9.7 months. The estimated 12-month survival was
75% and the MST had not been reached at the time of
publication.231
In a randomized phase III trial, advanced stage NSCLC
patients with an ALK fusion who failed one prior platinumbased treatment were treated with crizotinib (ALK-TKI) or
single agent pemetrexed or docetaxel.232 The median PFS
was 7.7 months in the crizotinib group compared with 3
months in the chemotherapy group (HR 0.49). The response
rate favored crizotinib treatment (65% vs. 20%), even
though there was no significant difference in survival
between the two treatment arms. The FDA has approved
ceritinib for the treatment of NSCLC patients with an ALK
fusion who were previously treated with crizotinib, to which
some cancers develop resistance.232a,232b
The Lung Cancer Mutation Consortium consists of 14
cancer centers in the United States and is sponsored by the
National Cancer Institute. These centers have tested more
than 1000 lung adenocarcinomas to look for driver mutations in 10 genes with a goal of determining treatment
based on the molecular subtypes.233 A driver mutation was
detected in 63% of 733 fully genotyped cases. The driver
mutations identified were KRAS (25%), activating EGFR
(15%), ALK rearrangements (8%), BRAF (2%), HER2 (2%),
PIK3CA (1%), and MET amplification (1%). Results were
used to select targeted therapy or targeted therapy trials in
279 patients with a driver mutation (28% of 1007). This
study demonstrated the potential for multiplex genomic
testing in patients with advanced NSCLC and is certainly
the direction for the future.
Recently, joint guidelines by the College of American
Pathologists, International Association for the Study of
Lung Cancer, and the Association of Molecular Pathology
have recommended that all patients with advanced stage
adenocarcinomas should be tested for EGFR and ALK mutations and patients should not be excluded from testing based
on clinical characteristics. These results should be used to
select patients for targeted therapy with EGFR-TKIs or ALKTKIs. Ideally, this testing should be performed before initial
treatment of advanced stage lung cancer.234 In addition to
targeted therapy based on mutation analysis, immunotherapy is a promising future direction in therapy for NSCLC.
There are several large clinical trials underway using vaccines and checkpoint inhibitors which may provide additional therapeutic options.234a
SMALL CELL LUNG CANCER
SCLC accounts for approximately 15% of all lung cancers.
This cell type has the strongest association with cigarette
smoking and is rarely observed in a never-smoker. It is the
cell type most commonly associated with paraneoplastic
syndromes such as the syndrome of inappropriate (excessive)
antidiuretic hormone secretion (SIADH), ectopic corticotropin
secretion, Lambert-Eaton myasthenic syndrome (LEMS), and
sensory neuropathy.
SCLC usually presents as a centrally located mass in the
hilum on chest radiograph (eFig. 53-21) and may be associated with obstructive pneumonia. In 5% or fewer cases,
SCLC may present as a solitary pulmonary nodule/mass
(eFig. 53-22). SCLC is generally staged according to the
Veterans Administration Staging System, and classified as
limited disease (LD) or extensive disease (ED). LD is confined
to one hemithorax, the mediastinum, and the ipsilateral
supraclavicular lymph nodes, and the disease can be encompassed adequately in a safe radiation portal.235 ED is any
disease spread beyond these limits. Malignant pleural effusion or disease extending to the contralateral supraclavicular or hilar lymph nodes is generally considered to be ED.
More recently, it has been proposed that the new TNM
staging system (7th edition) should also be used for small
cell lung cancer. The clinical stage groupings of I to IV were
predictive of overall survival and the findings were validated in a cohort from the Surveillance Epidemiology and
End Results registry236 and the California Cancer Registry.237 The survival rate for patients with LD with pleural
effusions was intermediate between those with ED and LD
without pleural effusions. The TNM staging is most helpful
in potentially resectable patients with T1-2NO disease.
Accordingly, it would be advisable to use both the TNM for
tumor registries and clinical trials to define patients with
minimal disease.
After establishing the histologic diagnosis of SCLC,
patients are usually staged with MRI of the brain, CT of the
chest (through the adrenal glands), and bone scan or PET.
In an evidence-based review of the literature, staging using
PET was compared with conventional staging using
non-PET imaging. Of 267 patients with LD by conventional
imaging, 16% were upstaged by PET. Of 199 patients with
ED, PET resulted in 11% being down-staged. In total, staging
with PET improves the accuracy of initial staging and
radiotherapy planning.235 If a PET scan is obtained, then a
bone scan may be omitted. In the unusual case when SCLC
presents as a peripheral nodule, the treatment of choice is
surgical resection followed by adjuvant chemotherapy and
possibly sequential thoracic radiotherapy. Careful preoperative staging should be performed in these individuals to
rule out metastatic disease. Pre-resection mediastinoscopy
should also be performed in all patients being considered for
resection with curative intent. If there are mediastinal node
metastases, then surgery should be abandoned, and the
patient treated with concurrent chemoradiotherapy as outlined later. The 5-year survival for peripheral SCLC that is
treated with surgery and adjuvant therapy is approximately
40% to 50%.238,239 Approximately one third of patients have
LD at diagnosis. LD-SCLC has a response rate of 70% to 80%
with standard chemotherapy and thoracic radiotherapy
(eFig. 53-23), and a complete clinical response of 50% to
60%. In a meta-analysis of trials with chemotherapy alone
versus combined chemotherapy and thoracic radiotherapy,
survival was significantly better with combined modality
therapy. A meta-analysis evaluated the timing of thoracic
radiotherapy.240 Early thoracic radiotherapy (<9 weeks from
the start of chemotherapy) resulted in a 5.2% increase in
2-year survival. The interval from start of treatment to the
end of radiotherapy was also identified as an important
predictor of outcome.241 Accordingly, data suggest that thoracic radiotherapy should begin early and be completed
quickly.235 Chemotherapy usually consists of a platinumbased regimen. The two most commonly used regimens are
etoposide and cisplatin or etoposide and carboplatin. Chemotherapy beyond four to six cycles has not been shown to
prolong survival.
The National Comprehensive Cancer Network and the
ACCP guidelines recommend treatment with four to six
cycles of a platinum-based chemotherapy with either cisplatin or carboplatin plus either etoposide or irinotecan.235
Multiple trials have evaluated a number of the novel molecularly targeted agents but to date none have shown improved
outcomes when added to standard treatment of small cell
lung cancer.242 A number of trials evaluating insulin-like
growth factor receptor inhibitors, antiangiogenesis, and
immunomodulatory drugs are under evaluation.
If a patient with SCLC achieves a complete remission,
then there is a 50% chance of development of cranial
metastasis within the next 2 years. A meta-analysis of
seven randomized trials of prophylactic cranial irradiation
(PCI) versus no PCI for patients in complete remission
reported an observed beneficial effect after PCI, with a 5.4%
increase in absolute survival (20.7% vs. 15.3%) at 3 years.243
The major questions raised by the meta-analysis concern the
optimal dose of PCI and the neuropsychological sequelae.
PCI is recommended in patients who achieve a complete
remission with initial therapy. PCI has also been shown to
result in a survival advantage in patients with ED-SCLC who
achieve a complete or partial response to initial therapy.244
PCI at 25 Gy in 10 fractions is the standard dose fractionation used in SCLC.245
When patients relapse after initial therapy, the median
survival is 3 to 4 months. There are no cures with secondline therapy. If a patient has been off treatment for 6 months
or longer, then it is reasonable to use the same agents that
he or she received initially. If initial therapy did not include
a platinum agent, then second-line therapy should be with
a platinum-containing doublet. Currently, the only drug
approved for second-line treatment of SCLC by the FDA is
single-agent topotecan.235,246 Other single agents such as
oral etoposide, paclitaxel, docetaxel, irinotecan, gemcitabine, and amrubicin are active but are not yet approved
by the FDA for second-line treatment of SCLC. Amrubicin
is commercially available and approved for second-line
treatment in Japan but is not available in the United States.
No molecularly targeted therapy has been approved for
SCLC in either the first-line or second-line setting.
PALLIATIVE CARE
Although much of this chapter is devoted to efforts to cure
lung cancer, most patients will eventually succumb to their
disease. Although pulmonologists are adept at providing
supportive care in the intensive care unit, caring for the
ambulatory dying patient with lung cancer requires special
consideration (see Chapter 104). There is a vast literature
on ambulatory pain management, the use of interventional
pulmonary techniques such as tumor ablation and stent
placement to relieve malignant airway obstruction (see
Chapter 19), and the use of hospice to provide end-of-life
care in the home setting. With the tools now available to
physicians, patients need not suffer debilitating cough,
nausea, dyspnea, or pain. Pulmonologists are encouraged
to provide “aggressive palliation” with the same conviction
that they provide treatments for critically ill patients in the
intensive care unit.247
SPECIAL CONSIDERATIONS IN
LUNG CANCER
SUPERIOR SULCUS TUMORS AND
PANCOAST SYNDROME
Pancoast syndrome is a constellation of symptoms and
signs that include shoulder and arm pain along the distribution of the eighth cranial nerve trunk and first and
second thoracic nerve trunks, Horner syndrome, and weakness and atrophy of the hand.248-250 The underlying cause
is usually local extension of an apical lung tumor located
in the superior pulmonary sulcus (Pancoast tumor) (see
eFig. 53-17). Pancoast syndrome is present in approximately one third of patients with superior sulcus tumors.
The most common cause of this symptom complex is
NSCLC; however, SCLC and a number of other types of
tumors and infections may rarely present in this manner.248
957
958
B
*
A
C
Figure 53-4 Superior sulcus (Pancoast) tumor. A, Frontal chest radiograph shows a mass at the extreme right pulmonary apex. Axial (B) and coronal
(C) enhanced chest CT shows a mass (arrow) at the right apex, arising from the superior sulcus region, identified by the presence of the subclavian artery
(arrowheads). Note first rib destruction (double arrowheads, B). Right paratracheal lymphadenopathy (*, C) is present. (Courtesy Michael Gotway, MD.)
The most common initial symptom is shoulder pain, which
is produced by tumor involvement of the parietal pleura,
brachial plexus, vertebral bodies, and first, second, and
third ribs. The pain may radiate along the upper back or
shoulder into the axilla and along the distribution of the
ulnar nerve. Patients are commonly treated for arthritis or
bursitis of the shoulder for months before the correct diagnosis is determined. Horner syndrome consists of ptosis,
miosis, and anhidrosis and is caused by the invasion of the
paravertebral sympathetic chain and the inferior cervical
(stellate) ganglion.248 The intrinsic muscles of the hands
may become weak and atrophied as the tumor progresses.
With further extension through the intervertebral foramina, spinal compression and paraplegia may develop.
The chest radiograph may show an apical tumor (Fig.
53-4A), although in some cases, a tumor can be identified
only on chest CT (Fig. 53-4B and C; see eFig. 53-18A). If
the diagnosis is suspected but the chest radiograph is negative, then a chest CT scan should be obtained (see eFigs.
53-17 and 53-18A). CT also provides additional information about the extent of the tumor (see Fig. 53-4B) and is
especially helpful in identifying other pulmonary nodules
and mediastinal adenopathy (see Fig. 53-4C). MRI of the
chest is considered to be superior for evaluating patients
with superior sulcus tumors because of better assessment
of invasion through the pleura and subpleural fat, better
evaluation of plexus involvement (see eFig. 53-18B and C),
and better definition of subclavian vessel involvement.251
Magnetic resonance angiography may give the best assessment of vascular invasion of the subclavian vessels. Flexible
fiberoptic bronchoscopy is frequently the first diagnostic
test for apical tumors and has a diagnostic yield of approximately 50%.252 TTNA has a very high diagnostic yield
(>90%) even if the bronchoscopy is nondiagnostic.253 Superior sulcus tumors are usually staged as T3N0M0 (stage IIB)
or higher depending on size of the tumor (T3 or T4) and
extent of lymph node involvement. In a large series from M.
D. Anderson, 25% of patients were stage IIB, 22% were
IIIA, and 53% were stage IIIB (T4 or N3).254 Some patients
who were stage IV at diagnosis were excluded from that
report. It is estimated that one third to one half of all superior sulcus tumors have identifiable distant metastasis at
diagnosis. In addition to the stage of disease and performance score, other important poor prognostic factors
include weight loss and vertebral body or supraclavicular
involvement. The presence of N1 or N2 nodal involvement
and incomplete resections have a worse prognosis.254,255 In
patients treated for localized disease (stage IIB or IIIB), the
brain is the most common site of relapse.256
In the past, the most common treatment for localized
superior sulcus tumors due to NSCLC was preoperative
radiotherapy of 30 to 50 Gy followed by resection. This
resulted in a 5-year survival of 25% to 35%. The current
standard of practice is to perform neoadjuvant chemoradiotherapy followed by resection. This is based on results
of the North America Intergroup Trial in which patients
with a negative mediastinoscopy were treated with two
cycles of etoposide and cisplatin chemotherapy and concurrent thoracic radiotherapy (45 Gy in 5 wk). In the
resected specimen, a pathologic complete response or
minimal microscopic disease was identified in 66% of
patients. The overall survival at 5 years was 44% and, for
those with a complete resection, 54%.256 In a phase II trial
in Japan, chemotherapy with mitomycin, vindesine, and
cisplatin with concurrent thoracic radiotherapy led to a
5-year survival of 56%.257 Although the optimal regimen
of treatment has not been proved, a reasonable choice is
that used in the U.S. Intergroup Trial study described
earlier.
SUPERIOR VENA CAVA SYNDROME
The blockage of blood flow in the SVC results in SVC syndrome.258 Bronchogenic carcinoma (see eFig. 83-1A-D and
A
B
C
Figure 53-5 SVC syndrome. A, Facial swelling in a patient with superior vena cava (SVC) syndrome. B, The same patient also presented with jagged,
blanching, violaceous plaques on the upper chest and abdomen. C, Chest radiograph shows a right mediastinal mass in another patient with SVC syndrome. (A and B, From Ratnarathorn M, Craig E: Cutaneous findings leading to a diagnosis of superior vena cava syndrome: a case report and review of the
literature. Dermatol Online J 17, 2011. Figs. 1 and 2; C, courtesy Michael Gotway, MD.)
Video 83-1) accounts for the vast majority of these cases in
older adults.259,260 In teenagers and young adults, SVC syndrome is usually due to non-Hodgkin lymphoma (see Fig.
83-2A-D and Video 83-2). Patients complain of dyspnea
and a sensation of fullness in the head and/or lightheadedness when bending over. They may also note facial
swelling. Cough, pain, and dysphagia are less frequent
symptoms. Physical examination findings included dilated
neck veins, a prominent venous pattern on the chest, facial
edema, and a plethoric appearance (Fig. 53-5A). The chest
radiograph typically shows widening of the mediastinum or
a right hilar mass (see Fig. 53-5B). Occasionally, it may be
normal. Dilated veins on the anterior chest wall and compression of the SVC (see eFigs. 83-1 and 83-2, and Videos
83-1 and 83-2) may be demonstrated with CT with intravenous contrast. SVC syndrome is not generally a medical
emergency, and patients should not be treated without a
tissue diagnosis. Bronchoscopy or mediastinoscopy can be
safely performed in the setting of SVC syndrome.261 Because
SCLC is chemosensitive, SVC syndrome due to SCLC is best
treated with chemotherapy; generally, after treatment,
symptoms start to resolve in 5 to 7 days.262 NSCLC is best
treated with concurrent chemoradiotherapy (see earlier
discussion of treatment of stage IIIA/IIIB NSCLC). If there
is a need for immediate relief of SVC obstruction, vascular
stenting should be strongly considered. A Cochrane metaanalysis reported that SVC stents relieved obstruction in
95% of cases.262 Stenting has been associated with a complication rate of 3% to 7%.
PARANEOPLASTIC SYNDROMES
Hormonal, neurologic, hematologic, or other remote effects
of cancer not related to the direct invasion, obstruction, or
metastatic effects of tumor are generally termed paraneoplastic syndromes. Paraneoplastic syndromes related to
bronchogenic carcinoma develop in 10% to 20% of patients
(Table 53-6).
MUSCULOSKELETAL EFFECTS
Clubbing of the digits may be a manifestation of lung
cancer or other diseases (see Fig. 16-3). Clubbing may
involve the fingers and toes and consists of selective enlargement of the connective tissue in the terminal phalanges.
Physical findings include loss of the angle between the
base of the nail bed and the cuticle, rounded nails, and
enlarged fingertips. Clubbing is an isolated finding and is
usually asymptomatic. Nonmalignant causes of clubbing
include pulmonary fibrosis, congenital heart disease, and
bronchiectasis.
Hypertrophic pulmonary osteoarthropathy (HPO) is an
uncommon process associated with lung cancer. HPO is
characterized by painful arthropathy that usually involves
the ankles, knees, wrists, and elbows and is most often symmetrical. The pain and arthropathy are caused by proliferative periostitis that involves the long bones but may also
affect metacarpal, metatarsal, and phalangeal bones.
Patients may have clubbing of fingers and toes in addition
to the painful arthralgias. The pathogenesis of HPO is
uncertain, but it may arise from a humoral agent. For
patients who smoke and have a new onset of arthralgias,
HPO must be considered. A radiograph of the long bones
(i.e., tibia and fibula) usually shows characteristic periosteal
new bone formation (Fig. 53-6B). A radionuclide bone scan
(see Fig. 53-6C) typically demonstrates diffuse uptake by the
long bones. Large cell and adenocarcinoma are the most
common histologic types associated with HPO (see Fig.
53-6A). The symptoms of HPO may resolve after thoracotomy, whether the primary cancer is resected or not. For
inoperable patients, treatment is with nonsteroidal antiinflammatory agents. Recently, case reports have observed
resolution or marked improvement of symptoms with
bisphosphonate treatment.263
Although still a topic of debate, population-based
studies from Scandinavia suggest a frequency of malignancy of 15% to 25% in patients with dermatomyositispolymyositis.264 The highest risk of malignancy is in the first
959
960
Table 53-6 Paraneoplastic Syndromes Associated with
Bronchogenic Carcinoma
System
Paraneoplastic Syndrome
Musculoskeletal
Clubbing
Hypertrophic osteoarthropathy
Polymyositis
Osteomalacia
Myopathy
Dermatomyositis
Acanthosis nigricans
Pruritus
Erythema multiforme
Hyperpigmentation
Urticaria
Scleroderma
Cushing syndrome
Syndrome of inappropriate secretion of
antidiuretic hormone
Hypercalcemia
Carcinoid syndrome
Hyperglycemia/hypoglycemia
Gynecomastia
Galactorrhea
Growth hormone excess
Calcitonin secretion
Thyroid-stimulating hormone
Lambert-Eaton myasthenic syndrome
Peripheral neuropathy
Encephalopathy
Myelopathy
Cerebellar degeneration
Psychosis
Dementia
Thrombophlebitis
Arterial thrombosis
Nonbacterial thrombotic endocarditis
Thrombocytosis
Polycythemia
Hemolytic anemia
Red cell aplasia
Dysproteinemia
Leukemoid reaction
Eosinophilia
Thrombocytopenic purpura
Cutaneous
Endocrinologic
Neurologic
Vascular/
hematologic
Miscellaneous
Cachexia
Hyperuricemia
Nephrotic syndrome
2 years after the diagnosis of dermatomyositis-polymyositis.
A reasonable approach to cancer surveillance in these
patients is a careful history and physical examination, chest
radiograph, basic laboratory tests, and age-appropriate
cancer screening examinations. Other tests should be based
on abnormalities detected during the basic evaluation.
HEMATOLOGIC EFFECTS
Anemia is common in patients who have lung cancer and
may be caused by iron deficiency, chronic disease, or bone
marrow infiltration. Eosinophilia is more often associated
with Hodgkin disease but may also be seen in patients with
lung cancer. Production of various cytokines by neoplastic
cells may result in eosinophilia, leukocytosis, or thrombocytosis, of which thrombocytosis is by far the most common.
Many of the hematologic effects of lung cancer do not lead
to clinical sequelae, and specific hormones or antibodies
responsible for the effects are typically not found.
The association of deep venous thrombosis and malignancy was described by Trousseau more than a century
ago, and lung cancer is the most common malignancy associated with hypercoagulability. The causes of the hypercoagulable state remain poorly understood. One large study
documented a clinically significant association of idiopathic
thrombosis with the subsequent development of overt
cancer; however, other investigators concluded that the literature does not enable firm recommendations about
whether to screen for a malignant neoplasm in patients
who have unexplained venous thromboembolism.265
Thromboembolism in the patient who has malignancy is
often refractory to warfarin treatment, and treatment with
low-molecular-weight heparin (LMWH) on a long-term basis
is likely more effective. In a randomized trial, patients with
cancer and deep vein thrombosis, pulmonary embolism, or
both were randomized to receive LMWH (dalteparin) subcutaneously once daily or oral warfarin daily for 6 months.266
At 6 months, the probability of recurrent thromboembolism was 9% with dalteparin treatment and 17% with warfarin, a difference that was highly significant. The risks of
major bleeding or any bleeding were not different in the two
groups. The other advantage of LMWH is that it is not necessary to monitor the anticoagulant effect, except in some
patients with renal insufficiency. A recent Cochrane analysis concluded that, for long-term treatment in patients with
cancer, LMWH reduced venous thromboembolism events,
but not death, as compared with vitamin K antagonists.
There was no significant difference in the risk of bleeding267
(see Chapter 57).
HYPERCALCEMIA
Hypercalcemia of malignancy may arise from a bony
metastasis, accelerated bone resorption, decreased bone
deposition, or increased renal tubular reabsorption of
calcium, but, most commonly, is due to secretion by the
tumor of a parathyroid hormone–related protein (PTHrP) or
other bone-resorbing cytokine (see Chapter 95). Lung
cancer is the most common solid tumor associated with
hypercalcemia, but other cancers also have an association,
such as kidney, breast, and head and neck cancer, myeloma,
and lymphoma. In one study of 690 consecutive lung
cancers, 2.5% of cases had tumor-induced hypercalcemia.268 Squamous cell histology is the most common cell
type associated with hypercalcemia, but hypercalcemia
does not rule out other lung cancers such as adenocarcinoma or, very rarely, small cell carcinoma. Generally, lung
cancer patients with hypercalcemia have advanced disease
(stage III or IV) and are unresectable.
Symptoms of hypercalcemia include anorexia, nausea,
vomiting, constipation, lethargy, polyuria, polydipsia, and
dehydration. Confusion and coma are late manifestations,
as are renal failure and nephrocalcinosis. Cardiovascular
effects include shortened QT interval, broad T wave, heart
block, ventricular arrhythmia, and asystole. Individual
patients may manifest any combination of these signs and
symptoms in various degrees.
Accelerated bone resorption is caused by activation of
osteoclasts by cytokines or PTHrP in most cases. Serum
parathyroid hormone levels are usually normal or low, but
an elevated level of PTHrP can be detected in the serum in
A
B
C
Figure 53-6 Lung carcinoma and hypertrophic osteoarthropathy. A, Frontal chest radiograph shows a left lung malignancy (arrow). B, Radiograph of
the tibia and fibula shows diaphyseal periosteal reaction (arrowheads). C, Radionuclide bone scan shows fairly symmetric, bilateral lower extremity tracer
uptake, consistent with hypertrophic osteoarthropathy. (Courtesy Michael Gotway, MD.)
approximately one half of these patients.268 Cytokines or
PTHrP are secreted autonomously by the tumor. Not only
does PTHrP cause renal calcium reabsorption, but also it
interferes with renal mechanisms for reabsorption of
sodium and water, with resultant polyuria. Polyuria and
vomiting result in dehydration; decreases in glomerular filtration further aggravate the hypercalcemia.
While most patients who have a serum calcium of 12 to
13 mg/dL or higher are treated, mild elevation of serum
calcium may not require treatment, so the decision is based
on the patient’s symptoms. For patients who have widely
metastatic and incurable malignancy, it may be most appropriate to give supportive care only and not treat the hypercalcemia. The average life expectancy in this situation is 30
to 45 days, even with aggressive treatment.269
The four basic goals of treatment are to (1) correct dehydration, (2) increase renal excretion of calcium, (3) inhibit
bone resorption, and (4) treat the underlying malignancy.
Because of the polyuria, patients with hypercalcemia are
usually volume-depleted. Initial treatment is with intravenous normal saline, using 3 to 6 L/24 hr as tolerated, with
careful attention to volume status. Previously, a loop
diuretic such as furosemide or ethacrynic acid was added to
maximize calcium excretion but has become less commonly
used due to the efficacy of the bisphosphonates in inhibiting bone resorption. Thiazide diuretics are not used because
they increase calcium reabsorption in the distal tubule.
Fluids and diuretics generally result in only a mild decrease
of the calcium; additional treatment is needed to inhibit the
accelerated bone resorption. The bisphosphonates have a
high affinity for bone and inhibit osteoclast activity. Zoledronate, a newer bisphosphonate, is the most effective; the
usual dose is 4 mg given intravenously over 15 minutes.270
Normal calcium levels are achieved within 4 to 10 days
in 85% of patients and last a median of 30 to 40 days.
Adverse effects are generally mild and transient and include
fever, hypophosphatemia, asymptomatic hypocalcemia
and, occasionally, renal failure. Calcitonin inhibits bone
961
962
resorption, increases renal calcium excretion, and has a
rapid onset of action, but the duration of action is
short lived. Calcitonin is a relatively weak agent and, when
used alone, does not usually normalize the serum calcium
of patients who have marked hypercalcemia. Use of calcitonin is appropriate when the calcium is greater than
14 mg/dL or needs to be lowered urgently (onset of action
is 4 to 6 hours) while waiting for the more effective but
slower acting agents to take effect or when relief of bone
pain is desired. The effects of calcitonin and bisphosphonates are additive. Tachyphylaxis to calcitonin may be seen
48 hours after administration. Other agents such as gallium
nitrate or plicamycin have been used to treat hypercalcemia
but have not generally been adopted as first-line therapies
because of inconvenience of administration schedules or
associated toxicities.
SYNDROME OF INAPPROPRIATE ANTIDIURETIC
HORMONE SECRETION
Hyponatremia is noted at the time of presentation in
approximately 15% of patients with SCLC and 1% of
patients with NSCLC and, in most cases, is due to ectopic
production of arginine vasopressin by the cancer cells.271
Under normal conditions, antidiuretic hormone (vasopressin) is secreted in the anterior hypothalamus and exerts its
action on the renal collecting ducts by enhancing the flow
of water from the lumen into the medullary interstitium,
thereby concentrating the urine. The criteria for the diagnosis of SIADH include (1) hyponatremia associated with
serum hypo-osmolality (<275 mOsm/kg), (2) inappropriately elevated urine osmolality (>200 mOsm/kg) relative to
serum osmolality; (3) elevated urine sodium (>20 mEq/L);
(4) clinical euvolemia without edema; (5) normal renal,
adrenal, and thyroid function. The serum uric acid is usually
low, and the urine osmolality–to–serum osmolality ratio is
frequently greater than 2.
The severity of symptoms is related to the degree of hyponatremia and the rapidity of the fall in serum sodium. In
one large series of patients with SIADH, only 27% had signs
or symptoms of hyponatremia despite a median sodium of
117 mEq/L (range, 101 to 129 mEq/L). Symptoms of hyponatremia include anorexia, nausea, and vomiting. With a
rapid onset of hyponatremia, symptoms caused by cerebral
edema may include irritability, restlessness, personality
changes, confusion, coma, seizures, and respiratory arrest.
In minimally symptomatic or asymptomatic patients,
fluid restriction of 500 to 1000 mL/24 hr is the initial
treatment of choice. Conivaptan is an intravenous vasopressin receptor antagonist that has been shown to be
useful in correcting hyponatremia but its use is limited to
hospitalized patients. The oral vasopressin receptor antagonist tolvaptan is now available for clinically significant
hypervolemic and for euvolemic hyponatremia (serum
sodium < 125 mEq/L or less marked hyponatremia that is
symptomatic and has resisted correction with fluid restriction). It should not be used in patients requiring intervention to raise serum sodium urgently to prevent or to treat
serious neurologic symptoms.272-274 If further treatment
is needed, oral demeclocycline (900 to 1200 mg/day)
can be considered. Demeclocycline induces a nephrogenic
diabetes insipidus and blocks the action of antidiuretic
hormone on the renal tubule, thereby increasing water
excretion. The onset of action varies from a few hours to a
few weeks, so this drug is not recommended for acute emergency treatment. Demeclocycline has potential kidney toxicity. In patients who have more severe or life-threatening
symptoms (serum sodium < 115 mEq/L), treatment consists of intravenous saline, supplemental potassium, and
diuresis with loop diuretics such as furosemide or ethacrynic acid. With severe confusion, convulsions, or coma,
it may be appropriate to treat with 300 mL of 3% saline
given over 3 to 4 hours in combination with a loop diuretic
(saline without a diuretic will not increase the sodium
concentration).
Rapid correction of the sodium may have life-threatening
consequences, and caution is advised.275 The rate of correction of the sodium is best limited to a maximum of
12 mEq/L/day, until a level of 120 to 130 mEq/L is reached.
Faster correction has been associated with the development
of central pontine myelinolysis, which may result in quadriplegia, cranial nerve abnormalities that manifest as pseudobulbar palsy, alteration in mental status, and subsequent
death. Accordingly, in the course of treating hyponatremia,
the serum sodium must be monitored frequently to ensure
that correction is not too rapid. For patients with SIADH
due to SCLC, treatment with chemotherapy should be initiated as soon as possible and is likely to result in improvement in the hyponatremia within a few weeks. After an
initial response to chemotherapy, SIADH may recur when
the tumor relapses.
ECTOPIC CORTICOTROPIN SYNDROME
Ectopic production of corticotropin or corticotropinreleasing hormone with associated Cushing syndrome has
been identified in patients with SCLC, carcinoid tumor
(lung, thymus, or pancreas), and neurocrest tumors such
as pheochromocytoma, neuroblastoma, and medullary
carcinoma of the thyroid.276 Of those with ectopic corticotropin secretion, SCLC accounts for 75% of cases, although
Cushing syndrome develops in only 1% to 2% of patients
with SCLC. Cushing syndrome is seldom caused by
NSCLC.
Classic features of Cushing syndrome include truncal
obesity, striae, rounded (moon) facies, dorsocervical fat pad
(buffalo hump), myopathy and weakness, osteoporosis, diabetes mellitus, hypertension, and personality changes.
However, the rapid growth of SCLC means that patients are
more likely to present with edema, hypertension, and muscular weakness than with the classic features of Cushing
syndrome. Hypokalemic alkalosis and hyperglycemia are
usually present. Patients with SCLC and Cushing syndrome
appear to have shortened survival compared to those
without the syndrome, perhaps because of more frequent
opportunistic infections.
The best screen for Cushing syndrome is the 24-hour
urine free cortisol measurement. Elevation of cortisol production, lack of suppression with high-dose dexamethasone, and plasma corticotropin levels greater than 200 pg/
mL (40 pmol/L) are highly suggestive of ectopic corticotropin as the cause of Cushing syndrome in the absence of a
pituitary adenoma. The plasma level of corticotropin is
elevated in many, but not all, patients.
Treatment of Cushing syndrome due to ectopic corticotropin has included adrenal enzyme inhibitors such as
metyrapone, aminoglutethimide, and ketoconazole, given
alone or in combination. Ketoconazole given orally at a
dosage of 400 to 1200 mg/day or metyrapone 250 to
750 mg three times per day may control hypercortisolism
within a few days to weeks, but the response is variable.277
Dose adjustments are based on achieving normal urinary
free cortisol levels or morning plasma cortisols of 7 to 11
μg/mL. Symptomatic hypoadrenalism may result from
treatment, and some authorities recommend a replacement
dose of glucocorticoid when an enzyme inhibitor is started.
When Cushing syndrome arises from SCLC, it is advisable
to proceed with appropriate chemotherapy and carefully
watch for superimposed infections, as for any patient who
is receiving high-dose corticosteroids. Cushing syndrome
related to a bronchial carcinoid or thymic carcinoid is best
treated by surgical resection of the tumor.
NEUROLOGIC EFFECTS
The paraneoplastic neurologic syndromes associated with
lung cancer, mostly small cell type, are variable and include
LEMS, subacute sensory neuropathy, encephalomyelopathy, cerebellar degeneration, autonomic neuropathy, retinal
degeneration, and opsoclonus/myoclonus.278 The frequency
of any of these neurologic syndromes in SCLC is approximately 5%, and neurologic symptoms may precede the
diagnosis by months to years.279,280 Most patients with SCLC
who have an associated paraneoplastic syndrome have
LD-SCLC that may or may not be obvious on initial evaluation. Careful radiographic evaluation of the lungs and
mediastinum is indicated in a smoker who has a suspected
paraneoplastic neurologic syndrome. In this setting, even
subtle abnormalities of the mediastinum require a biopsy.
PET may help identify an occult lesion and facilitate biopsy
confirmation of the diagnosis.281,282 Many reports have suggested that patients with paraneoplastic neurologic syndromes have a better prognosis than those without the
paraneoplastic syndromes with similar stage and histology.
These paraneoplastic neurologic syndromes are thought
to be immune-mediated, based on the identification of a
number of antibodies in the serum that react with both the
nervous system and the underlying cancer.278 However, not
all patients with paraneoplastic syndromes have identifiable
antibodies in their serum. The literature is confusing
because of different names employed by various investigators. The anti-Hu antibody is the same as antineuronal
nuclear antibody type 1 (ANNA-1), and the anti-Ri antibody
is identical to ANNA-2. Both of these antibodies, but predominantly anti-Hu, have been associated with SCLC.
Anti-Hu is an IgG antibody found in the sera and cerebrospinal fluid and binds to the nuclei of all neurons in the
central and peripheral nervous system, including the
sensory and autonomic ganglia, the myenteric plexus, and
cells of the adrenal medulla. Such antibodies should not be
confused with the anti-Purkinje cell antibody (anti-Yo),
which is characteristically found in patients who have subacute cerebellar degeneration as a manifestation of gynecologic malignancy or breast cancer. The CRMP-5 antibody,
known as anti-CV-2, has also been associated with SCLC
and thymomas.278
In a review of 162 sequential patients who had elevated
anti-Hu (ANNA-1), 142 (88%) were proved to have cancer,
132 of whom had SCLC.280 In 97% of these cases, the neurologic syndrome preceded the diagnosis of SCLC, usually
by less than 6 months but, in 20%, by more than 6 months.
Of special note is that 90% of cases had disease limited to
the lung or to the lung and mediastinum (LD-SCLC). In a
report from Europe, 144 patients of 200 with anti-Hu antibodies had a tumor in the chest.279 Of these, 111 were
proved to be SCLC. In one large series, ANNA-1 antibodies
were identified in 16% of all patients with SCLC. These antibodies were associated with limited-stage disease, complete
response to therapy, and longer survival compared with
patients who had SCLC and no ANNA-1 antibody. These
neurologic syndromes seldom improve with treatment, so
the goal is to prevent progression by starting treatment of
the underlying tumor as soon as possible.
Less common manifestations of neurologic paraneoplastic syndromes are orthostatic hypotension and intestinal
dysmotility. The gastrointestinal symptoms may present as
nausea, vomiting, abdominal discomfort, or altered bowel
habits suggestive of intestinal pseudo-obstruction. Many of
these patients present with gastrointestinal symptoms and
significant weight loss before the diagnosis of SCLC.
LEMS is characterized by proximal muscle weakness,
hyporeflexia, and autonomic dysfunction.283,284 Cranial
nerve involvement may be present and does not differentiate LEMS from myasthenia gravis. LEMS has been strongly
associated with antibodies directed against P/Q-type
presynaptic voltage-gated calcium channels (anti-VGCC antibodies) of peripheral cholinergic nerve terminals. These
anti-VGCC antibodies, identified in more than 90% of
patients with LEMS, block the normal release of acetylcholine at the neuromuscular junction. (In contrast, myasthenia gravis is associated with anti–acetylcholine receptor
antibodies, which are present in approximately 90% of
myasthenic patients.)
Of patients with LEMS, malignancy is present in approximately half and, of the cancers, SCLC is by far the most
common. And yet, when SCLC patients are studied prospectively, LEMS is uncommon. In a recent study of 63 patients
with SCLC examined prospectively, only 3% had clinical and
electrophysiologic signs of LEMS, 8% had elevated antiVGCC antibodies, and 26% had other neurologic symptoms
unrelated to LEMS.285 The diagnosis of LEMS is based on
characteristic electromyographic findings that show a small
amplitude of the resting compound muscle action potential
and facilitation with rapid, repetitive, supramaximal nerve
stimulation or after brief exercise of the muscle. A singlefiber electromyogram is optimal for making the diagnosis.
LEMS is the predominant paraneoplastic neurologic syndrome that may improve with successful treatment of the
associated lung cancer. The use of acetylcholinesterase
inhibitors is of limited benefit in LEMS.286 However, diaminopyridine, which enhances the release of acetylcholine,
has been used with sustained improvement over months
in the majority of patients with LEMS with or without
cancer.287
Opsoclonus consists of rapid involuntary eye movements
that are conjugate in vertical and horizontal directions.
In patients with SCLC, NSCLC, or other solid tumors,
it is frequently associated with myoclonus. While the
963
964
anti-Hu antibody has been identified in patients with
SCLC and opsoclonus/myoclonus, the syndrome of
opsoclonus/myoclonus is the primary presentation of
paraneoplastic cerebellar degeneration associated with
anti-Ri antibodies.288,289
Key Points
■
■
■
■
■
■
■
Lung cancer currently claims more lives than breast,
colon, and prostate cancer combined and is the
number-one cancer killer of both men and women in
the United States and worldwide.
Routine screening for lung cancer with low-dose CT
scanning is now recommended for certain at-risk
groups.
Accurate staging of lung cancer is critical because
treatment strategies and outcome vary significantly by
stage. The pulmonologist is uniquely positioned to
stage lung cancer appropriately.
In general, for non–small cell lung cancer, early lung
cancer (stage I) is treated with surgery alone, stage II
lung cancer is treated with surgery followed by adjuvant chemotherapy, locally advanced lung cancer
(stage IIIA and B) is treated with a combination of
chemotherapy and radiotherapy, and metastatic
disease (stage IV) is treated with chemotherapy alone.
For small cell lung cancer, localized disease (disease
within one hemithorax that can be encompassed in a
radiation port) is treated by chemoradiotherapy;
extensive disease is treated with chemotherapy alone.
A certain subgroup of lung cancer patients with an
activating mutation of the tyrosine kinase domain of
the epidermal growth factor receptor respond to tyrosine kinase inhibitors such as erlotinib or gefitinib.
Patients with an EML4-ALK translocation can respond
to the tyrosine kinase inhibitor, crizotinib.
Therapy targeted to block driver mutations is a major
advance in the approach to lung cancer therapy and
will be the focus for developing new treatments for
lung cancer.
Complete reference list available at ExpertConsult.
Key Readings
Annema JT, et al: Mediastinoscopy vs endosonography for mediastinal
nodal staging of lung cancer: a randomized trial. J Am Med Assoc
304:2245–2252, 2010.
Bach PB, et al: Benefits and harms of CT screening for lung cancer: a
systematic review. J Am Med Assoc 307:2418–2429, 2012.
Brunelli A, et al: Physiologic evaluation of the patient with lung cancer
being considered for resectional surgery: diagnosis and management of
lung cancer, 3rd ed. American College of Chest Physicians evidencebased clinical practice guidelines. Chest 143(5 Suppl):e166S–190S,
2013.
Jemal A, et al: Global cancer statistics. CA Cancer J Clin 61:69–90,
2011.
Jett JR, et al: Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians
evidence-based clinical practice guidelines. Chest 143(5 Suppl):e400S–
e419S, 2013.
Johnson B, et al: A multicenter effort to identify driver mutations and
employ targeted therapy in patients with lung adenocarcinomas: the
Lung Cancer Mutation Consortium (LCMC). J Clin Oncol (Suppl, abstract
8019), 2013.
Lindeman NI, et al: Molecular testing guideline for selection of lung cancer
patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the
College of American Pathologists, International Association for the
Study of Lung Cancer, and Association for Molecular Pathology. J Thorac
Oncol 8:823–859, 2013.
Mok TS, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957, 2009.
Ramnath N, Dilling TJ, Harris LJ, et al: Treatment of stage III non-small
cell lung cancer: diagnosis and management of lung cancer, 3rd ed:
American College of Chest Physicians. Chest 143(5 Suppl):e314S–
e340S, 2013.
Rivera P, Wahidi M, Mehta A: Establishing the diagnosis of lung cancer.
diagnosis and management of lung cancer, 3rd ed: American College of
Chest Physicians evidence-based clinical practice guidelines. Chest
143(5 Suppl):142S–165S, 2013.
Screening for Lung Cancer: U.S. Preventive Services Task Force recommendation statement draft: summary of recommendation and evidence, 2013.
Available at:: <http://www.uspreventiveservicestaskforce.org/uspstf13/
lungcan/lungcanart.htm>.
Silvestri G, Gonzalez A, Jantz M, et al: Methods for staging non-small cell
lung cancer—diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143:211S–250S, 2013.
Wang Memoli JS, Nietert PJ, Silvestri GA: Meta-analysis of guided bronchoscopy for the evaluation of the pulmonary nodule. Chest 142:385–
393, 2012.
53 • Clinical Aspects of Lung Cancer 964.e1
eFIGURE IMAGE GALLERY
B
A
C
eFigure 53-1 Lung carcinoma staging: false-positive CT and true-negative PET mediastinal lymph node assessment. A, Axial chest CT shows a right
upper lobe primary lung malignancy (arrow) and a mildly enlarged right paratracheal lymph node (arrowhead). Axial (B) and coronal (C) PET images show
intense metabolic activity within the right upper lobe neoplasm (arrows) but lack of tracer uptake in the right paratracheal node region (circle, B and C),
suggesting no tumor involvement in the latter location. Surgical resection confirmed the right paratracheal lymph nodes were free of tumor. (Courtesy
Michael Gotway, MD.)
A
B
C
eFigure 53-2 Lung carcinoma staging: false-positive CT and true-negative PET mediastinal lymph node assessment. A, Axial chest CT shows an
enlarged aortopulmonary window lymph node (arrow) in a patient with a left upper lobe primary lung malignancy, raising the possibility of N2 disease.
B and C, Axial fused PET images show intense metabolic activity within the left upper lobe lesion (arrow, B), but no significant tracer accumulation within
the aortopulmonary window lymph node (arrowhead, C). The aortopulmonary window lymph nodes were free of malignancy at pathologic analysis following surgical resection. (Courtesy Michael Gotway, MD.)
964.e2 PART 3 • Clinical Respiratory Medicine
A
B
C
E
D
F
eFigure 53-3 Lung carcinoma staging: false-negative CT and true positive PET mediastinal lymph node assessment. A, Axial chest CT shows a
peripheral lingular lobulated nodule (arrow) representing pulmonary adenocarcinoma. B, Axial fused PET image shows intense metabolic activity within
the lingular neoplasm (arrow). C and D, Axial unenhanced chest CT shows normal-sized left peribronchial (arrow, C) and mediastinal (arrow, D) lymph
nodes. E and F, Axial fused PET images show intense metabolic activity within these lymph nodes (arrows). Malignant infiltration of the lymph nodes was
shown at biopsy. (Courtesy Michael Gotway, MD.)
A
C
B
D
eFigure 53-4 Lung carcinoma staging: malignant pleural disease. A and B, Axial enhanced chest CT in a patient with primary lung malignancy shows
features of malignant pleural disease: circumferential, nodular pleural thickening (arrowheads). Right paratracheal lymphadenopathy (arrow) is present.
C and D, Axial fused PET images show tracer accumulation within both the pleural malignancy (arrowheads) and right paratracheal lymph node (arrow).
(Courtesy Michael Gotway, MD.)
A
B
eFigure 53-5 Lung carcinoma staging: malignant pleural disease/dry
pleural dissemination. A, Axial chest CT shows nodular thickening of the
right major fissure (arrows). B, Image from video-assisted thoracoscopic
surgery shows numerous pleural nodules (arrows). (Courtesy Michael
Gotway, MD.)
A
B
C
D
eFigure 53-6 False-positive PET in the assessment of suspected lung cancer in a patient with a solitary pulmonary nodule. Axial chest CT shown
in soft tissue (A) and lung (B) windows shows a lobulated, noncalcified right upper lobe nodule (arrows). Coronal fused (C) and whole-body (D) PET images
show significant tracer accumulation within the nodule (arrowheads), suggesting possible neoplasm. Biopsy revealed Mycobacterium scrofulaceum. (Courtesy Michael Gotway, MD.)
A
C
E
B
D
F
eFigure 53-7 False-negative PET in the assessment of suspected lung cancer in a patient with a solitary pulmonary nodule: limitations due to
low metabolic activity malignancy and spatial resolution. A, Fused PET image shows lack of significant tracer accumulation within a lobulated left
upper lobe nodule (arrow). B, Axial chest CT shown in lung windows, performed near the time of the PET scan, shows an indeterminate lobulated left
upper lobe nodule. C and D, Axial chest CT scans obtained 3 and 6 months, respectively, following A and B show growth in the left upper lobe nodule.
Biopsy subsequently confirmed primary lung malignancy. Lack of significant accumulation of tracer at PET imaging, even though the nodule exceeded
1 cm in size, was the result of low metabolic activity within this malignant nodule. Axial chest CT (E) and axial fused PET images (F) in a patient with
primary pulmonary malignancy show a small right base nodule (arrows). This small nodule shows no significant tracer accumulation at PET. The lesion
was followed with serial chest CT and subsequently showed growth. Primary pulmonary malignancy was ultimately proven at biopsy. (Courtesy Michael
Gotway, MD.)
A
B
eFigure 53-8 Positive impact of PET on lung carcinoma: stage migration from stage III to stage IV classification. A and B, Coronal whole-body fused
PET images in a patient with a left upper lobe pulmonary malignancy (large arrow, B) show ipsilateral mediastinal lymph node involvement (white arrowhead, B) and an unsuspected isolated contralateral rib metastasis (small arrow, A) and brain metastasis (black arrowhead, B). (Courtesy Michael Gotway,
MD.)
A
B
C
eFigure 53-9 Extrathoracic metastatic disease from lung carcinoma shown at CT. A, Caudal image from enhanced chest CT shows bilateral cystic
adrenal metastases (arrows). B, Enhanced neck CT shows an avidly enhancing left parotid nodule, proven on biopsy to reflect metastatic lung carcinoma.
C, Contrast-enhanced axial brain CT shows a peripherally enhancing brain metastasis (arrow) with surrounding vasogenic edema. (Courtesy Michael Gotway,
MD.)
eFigure 53-10 Lung cancer staging with PET: adrenal metastasis. Coronal PET shows a medial left lung malignancy (arrow) with an isolated right
adrenal metastatic focus (arrowhead). (Courtesy Michael Gotway, MD.)
A
B
C
eFigure 53-11 Lung cancer staging with PET: hepatic metastasis. Coronal (A), axial (B), and sagittal (C) PET imaging shows a left upper lobe pulmonary
malignancy (arrow, A) and ipsilateral mediastinal lymph node involvement (arrowhead) associated with an isolated hepatic metastatic focus (arrowheads,
B and C). (Courtesy Michael Gotway, MD.)
eFigure 53-12 Lung cancer staging with PET: osseous metastasis. Axial
PET image shows a medial left lung malignancy (black arrow) associated
with a vertebral body metastatic focus (white arrow). (Courtesy Michael
Gotway, MD.)
eFigure 53-13 Transthoracic percutaneous lung biopsy for the diagnosis of pulmonary malignancy. Axial chest CT image acquired during a
percutaneous biopsy procedure. The biopsy needle (arrowheads) has been
advanced to biopsy a nodule (arrow). (Courtesy Michael Gotway, MD.)
A
B
eFigure 53-14 T staging for primary pulmonary malignancy. A, T1a lung carcinoma: 8-mm lobulated nodule (arrow) in the inferior right middle lobe,
completely surrounded by lung. B, T2a lung carcinoma: 2.8-cm spiculated left upper lobe nodule (arrow), completely surrounded by lung parenchyma,
greater than 2 cm away from the carina, and without chest wall or parietal pleural invasion. (Courtesy Michael Gotway, MD.)
A
B
eFigure 53-15 T staging for primary pulmonary malignancy: locally restricted disease. T2a lung carcinoma: 3.8 cm left upper lobe spiculated mass,
completely surrounded by lung parenchyma, greater than 2 cm away from the carina, and without chest wall or parietal pleural invasion (A), and 4.8 cm
right upper lobe mass, completely surrounded by lung parenchyma, greater than 2 cm away from the carina, and without chest wall or parietal pleural
invasion (B). (Courtesy Michael Gotway, MD.)
A
B
C
eFigure 53-16 T staging for primary pulmonary malignancy: chest wall invasion. A, Axial chest CT displayed in bone windows shows a large right
upper lobe mass with clear erosion of the internal cortex of the rib (arrowheads). B and C, Axial and sagittal enhanced chest CT shows an avidly enhancing
subpleural left upper lobe mass extending into the soft tissues of the chest wall (arrows). (Courtesy Michael Gotway, MD.)
A
B
C
D
E
F
eFigure 53-17 Superior sulcus anatomy. Axial (A–C) and coronal (D–F) enhanced chest CT through the upper thorax shows the region of the superior
sulcus. A–C, Axial enhanced chest CT shows the region of the superior sulcus, extending from the inferior neck superiorly and bounded by the first rib
inferiorly and vertebral body medially, and containing structures such as the brachial plexus, stellate ganglion, apical pleura and Sibson fascia, subclavian
vein, and subclavian artery (arrowheads). (Courtesy Michael Gotway, MD.)
*
A
B
C
eFigure 53-18 Primary pulmonary malignancy arising in the superior sulcus. A, Axial enhanced chest CT shows a mass (*) in the superior sulcus. The
region of the superior sulcus on axial CT can be readily and quickly identified when the subclavian artery (arrowheads) and first rib (arrow) are seen. Coronal
T2-weighted (B) and T1-weighted (C) MRI shows the right upper lobe mass (arrows) extending cranially into the neck soft tissues, involving the brachial
plexus. (Courtesy Michael Gotway, MD.)
eFigure 53-19 T staging for primary pulmonary malignancy: locally advanced disease. Axial chest CT shows a large primary pulmonary malignancy
(arrowheads) in the superior segment of the right lower lobe, with a separate tumor nodule in the right upper lobe (arrow) (an ipsilateral nonprimary lobe),
consistent with T4 disease. (Courtesy Michael Gotway, MD.)
*
*
A
B
C
eFigure 53-20 Infiltrating lymphadenopathy versus discrete lymphadenopathy. A, Axial enhanced chest CT at the level of the carina shows confluent
soft tissue with areas of low attenuation (double arrowheads) occupying the right paratracheal and subcarinal spaces, extending toward the right peribronchial region. B and C, Axial enhanced chest CT shows discretely enlarged lymph nodes in the right paratracheal space (station 4R) (arrow, B), left
tracheobronchial angle (station 4L) (*, B), aortopulmonary window region (station 5) (arrowhead, B), and subcarinal space (station 7) (*, C). (Courtesy Michael
Gotway, MD.)
A
B
C
D
eFigure 53-21 Small cell carcinoma: typical imaging appearance. A, Frontal chest radiograph shows increased density and enlargement of the left
hilum (arrow). Coronal (B and C) and axial (D) enhanced chest CT shows confluent soft tissue surrounding and narrowing the left pulmonary artery
(arrowheads, B and C) and extending into the mediastinum. (Courtesy Michael Gotway, MD.)
A
B
eFigure 53-22 Small cell carcinoma presenting as a solitary pulmonary nodule. A, Axial chest CT shows a lobulated peripheral right upper lobe nodule.
Appearance suggests pulmonary malignancy, especially adenocarcinoma. B, Fused axial PET shows intense metabolic activity within the nodule. Biopsy
revealed small cell lung carcinoma. (Courtesy Michael Gotway, MD.)
A
B
eFigure 53-23 Small cell carcinoma: treatment response. A, Axial enhanced chest CT shows confluent left hilar (arrow) and mediastinal (arrowhead)
lymphadenopathy, proven to represent small cell carcinoma. B, Axial enhanced chest CT following therapy shows marked regression in the confluent
lymphadenopathy. (Courtesy Michael Gotway, MD.)
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53 clinical aspects of lung cancer

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