1. Lung Tumors
A variety of benign and malignant tumors may arise in the lung, but the vast majority (90% to 95%)
are carcinomas, about 5% are bronchial carcinoids, and 2% to 5% are mesenchymal and other
miscellaneous neoplasms.[42]
CARCINOMAS
Lung cancer is currently the most frequently diagnosed major cancer in the world and the most
common cause of cancer mortality worldwide. This is largely due to the carcinogenic effects of
cigarette smoke. Over the coming decades, changes in smoking habits will greatly influence lung
cancer incidence and mortality as well as the prevalence of various histologic types of lung
cancer.[115]
The number of new cases of lung cancer occurring in 2003 in the United States is estimated to be
171,900 (note that in 1950 it was 18,000), accounting for about 13% of cancer diagnoses. The
incidence rate is declining significantly in men, from a high of 86.5 per 100,000 in 1984 to 69.8 in
1998. In the 1990s, the increase among women reached a plateau, with incidence in 1998 at 43.4
per 100,000. The annual number of deaths from lung cancer in the United States is estimated to be
157,200 in 2003. During 1992 to 1998, mortality from lung cancer declined significantly (1.9% per
year) among men, while rates for women continued to increase but at a much slower pace (0.8%
per year). Since 1987, more women have died each year of lung cancer than of breast cancer,
which for over 40 years had been the major cause of cancer death in women. Decreasing lung
cancer incidence and mortality rates have most likely resulted from the decreased smoking rates
over the past 30 years. However, decreases in smoking patterns among women lag behind those
of men. Declines in adult tobacco use have slowed, as have declines in mortality under 45 years
old; tobacco use among youth increased considerably during the 1990s except in states with
vigorous control programs.
Cancer of the lung occurs most often between ages 40 and 70 years, with a peak incidence in the
fifties or sixties. Only 2% of all cases appear before the age of 40. The outlook for patients
diagnosed with lung cancer is dismal. The 1-year relative survival rate has increased from 34% in
1975 to 41% in 1997, largely owing to improvements in surgical techniques. However, the 5-year
rate for all stages combined is only 15%.
Etiology and Pathogenesis.
Carcinomas of the lung, similar to cancer at other sites, arise by a stepwise accumulation of
genetic abnormalities that transform benign bronchial epithelium to neoplastic tissue. Unlike many
other cancers, however, the major environmental insult that inflicts genetic damage is known. We
begin our discussion with the well known lung carcinogen—cigarette smoke.
Tobacco Smoking.

2. The evidence provided by statistical and clinical observations establishing a positive relationship
between tobacco smoking and lung cancer is overwhelming. Experimental data have also been
pursued, but this approach is limited by species differences.
Statistical evidence is most compelling: 87% of lung carcinomas occur in active smokers or those
who stopped recently. In numerous retrospective studies, there was an invariable statistical
association between the frequency of lung cancer and (1) the amount of daily smoking, (2) the
tendency to inhale, and (3) the duration of the smoking habit. Compared with nonsmokers, average
smokers of cigarettes have a 10-fold greater risk of developing lung cancer, and heavy smokers
(more than 40 cigarettes per day for several years) have a 60-fold greater risk. Women have a
higher susceptibility to tobacco carcinogens than men do. Cessation of smoking for 10 years
reduces risk but never to control levels. Epidemiologic studies also show an association between
cigarette smoking and carcinoma of the mouth, pharynx, larynx, esophagus, pancreas, uterine
cervix, kidney, and urinary bladder. Secondhand smoke, or environmental tobacco smoke,
contains numerous human carcinogens for which there is no safe level of exposure. Each year,
about 3000 nonsmoking adults die of lung cancer as a result of breathing secondhand smoke.[116]
Cigar and pipe smoking also increase risk, although much more modestly than smoking cigarettes.
The use of smokeless tobacco is not a safe substitute for smoking cigarettes or cigars, as these
products cause oral cancers and can lead to nicotine addiction.
Clinical evidence is obtained largely through observations of histologic changes in the lining
epithelium of the respiratory tract in habitual smokers. These sequential changes have been best
documented for squamous cell carcinoma, but they may also be present in other histologic
subtypes. In essence, there is a linear correlation between the intensity of exposure to cigarette
smoke and the appearance of ever more worrisome epithelial changes that begin with squamous
metaplasia and progress to squamous dysplasia, carcinoma in situ, and invasive carcinoma.
Experimental work has consisted mainly of attempts to induce cancer in experimental animals with
extracts of tobacco smoke.[117] More than 1200 substances have been counted in cigarette smoke,
many of which are potential carcinogens. They include both initiators (polycyclic aromatic
hydrocarbons such as benzo[a]pyrene) and promoters, such as phenol derivatives. Radioactive
elements may also be found (polonium-210, carbon-14, potassium-40) as well as other
contaminants, such as arsenic, nickel, molds, and additives. Protracted exposure of mice to these
additives induces skin tumors. Efforts to produce lung cancer by exposing animals to tobacco
smoke, however, have been unsuccessful. The few cancers that have developed have been
bronchioloalveolar carcinomas, a type of tumor that is not strongly associated with smoking in
humans.
Industrial Hazards.
Certain industrial exposures increase the risk of developing lung cancer. High-dose ionizing
radiation is carcinogenic. There was an increased incidence of lung cancer among survivors of the
Hiroshima and Nagasaki atomic bomb blasts. Uranium is weakly radioactive, but lung cancer rates
among nonsmoking uranium miners are 4 times higher than those in the general population, and
among smoking miners, they are about 10 times higher.

3. The risk of lung cancer is increased with asbestos. Lung cancer is the most frequent malignancy in
individuals exposed to asbestos, which has become a universally recognized carcinogen,
particularly when coupled with smoking.[66] Asbestos workers who do not smoke have a five times
greater risk of developing lung cancer than do nonsmoking control subjects, and those who smoke
have a 50 to 90 times greater risk. The latent period before the development of lung cancer is 10 to
30 years. Among asbestos workers, one death in five is due to lung carcinoma, 1 in 10 to pleural or
peritoneal mesotheliomas (discussed later), and 1 in 10 to gastrointestinal carcinomas.
Air Pollution.
Atmospheric pollutants may play some role in the increased incidence of lung carcinoma today.
Attention has been drawn to the potential problem of indoor air pollution, especially by radon.[118][119]
Radon is a ubiquitous radioactive gas that has been linked epidemiologically to increased lung
cancer in miners exposed to relatively high concentrations. The pathogenetic mechanism is
believed to be inhalation and bronchial deposition of radioactive decay products that become
attached to environmental aerosols. These data have generated concern that low-level indoor
exposure (e.g., in homes in areas of high radon in soil) could also lead to increased incidence of
lung tumors; some attribute the bulk of lung cancers in nonsmokers to this insidious carcinogen
( Chapter 9 ).[120]
Molecular Genetics.
Ultimately, the exposures cited previously are thought to act by causing genetic alterations in lung
cells, which accumulate and eventually lead to the neoplastic phenotype. It has been estimated
that 10 to 20 genetic mutations have occurred by the time the tumor is clinically apparent.[121]
As will be discussed below, for all practical purposes, lung cancers can be divided into two clinical
subgroups: small cell carcinoma and non-small cell carcinoma. Some molecular lesions are
common to both types, whereas others are relatively specific. The dominant oncogenes that are
frequently involved in lung cancer include c-MYC, K-RAS, EGFR, and HER-2/neu. The commonly
deleted or inactivated tumor suppressor genes include p53, RB, p16INK4a, and multiple loci on
chromosome 3p. At this locale, there are numerous candidate tumor suppressor genes, such as
FHIT, RASSF1A, and others that remain to be identified. Of the genetic alterations listed above,
p53 mutations are common to both small cell and non-small cell carcinomas. In contrast, small cell
cancers harbor more frequent alterations in c-MYC and RB, whereas non-small cell tumors are
associated with mutations in RAS and p16INK4a. Some of these differences are further highlighted in
the ensuing discussion.[122] Although certain genetic changes are known to be early (inactivation of
chromosome 3p suppressor genes) or late (activation of RAS), the temporal sequence is not yet
well defined. More importantly, certain genetic changes such as loss of chromosome 3p material
can be found in benign bronchial epithelium of patients with lung cancer, as well as in the
respiratory epithelium of smokers without lung cancers, suggesting that large areas of the
respiratory mucosa are mutagenized after exposure to carcinogens ("field effect"). On this fertile
soil, the cells that accumulate additional mutations ultimately develop into cancer.
Occasional familial clustering has suggested a genetic predisposition, as has the variable risk even
among heavy smokers. Attempts at defining markers of genetic susceptibility are ongoing and

4. have, for example, identified a role for polymorphisms in the cytochrome P-450 gene CYP1A1
( Chapter 7 ). People with certain alleles of CYP1A1 have an increased capacity to metabolize
procarcinogens derived from cigarette smoke and, conceivably, incur the greatest risk of
developing lung cancer. Similarly, individuals whose peripheral blood lymphocytes undergo
chromosomal breakages following exposure to tobacco-related carcinogens (mutagen sensitivity
genotype) have a greater than tenfold risk of developing lung cancer compared with controls.
Precursor Lesions.
Three types of precursor epithelial lesions are recognized: (1) squamous dysplasia and carcinoma
in situ, (2) atypical adenomatous hyperplasia, and (3) diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia. It should be noted that the term "precursor" does not imply that progression to
invasion will occur in all cases. Currently, it is not possible to distinguish between preinvasive
lesions that are likely to progress and those that will remain localized.
Classification.
Tumor classification is important for consistency in patient treatment and because it provides a
basis for epidemiologic and biological studies. The most recent classification of the World Health
Organization[115] has gained wide acceptance ( Table 15-10 ). Several histologic variants of each
type of lung cancer are described; however, their clinical significance is still undetermined, except
as mentioned below. The relative proportions of the major categories are:
? Squamous cell carcinoma (25% to 40%)
? Adenocarcinoma (25% to 40%)
? Small cell carcinoma (20% to 25%)
? Large cell carcinoma (10% to 15%)
Table 15-10 -- Histologic Classification of Malignant Epithelial Lung Tumors
Squamous cell carcinoma
Small cell carcinoma
Combined small cell carcinoma
Adenocarcinoma
Acinar; papillary, bronchioloalveolar, solid, mixed subtypes
Large cell carcinoma
Large cell neuroendocrine carcinoma
Adenosquamous carcinoma
Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
Carcinoid tumor

5. Typical, atypical
Carcinomas of salivary gland type
Unclassified carcinoma
The incidence of adenocarcinoma has increased significantly in the last two decades; it is now the
most common form of lung cancer in women and, in many studies, men as well.[42][123] The basis
for this change is unclear. A possible factor is the increase in women smokers, but this only
highlights our lack of knowledge about why women tend to show more adenocarcinomas. One
interesting postulate is that changes in cigarette type (filter tips, lower tar and nicotine) have
caused smokers to inhale more deeply and thereby expose more peripheral airways and cells (with
a predilection to adenocarcinoma) to carcinogens.[124] There may be mixtures of histologic patterns,
even in the same cancer. Thus, combined types of squamous cell carcinoma and adenocarcinoma
or of small cell and squamous cell carcinoma occur in about 10% of patients. For common clinical
use, however, the various histologic types of lung cancer can be clustered into two groups on the
basis of likelihood of metastases and response to available therapies: small cell carcinomas (most
often metastatic, high initial response to chemotherapy) versus non-small cell carcinomas (less
often metastatic, less responsive). The strongest relationship to smoking is with squamous cell and
small cell carcinoma.
Morphology.
Lung carcinomas arise most often in and about the hilus of the lung. About three fourths of the
lesions take their origin from first-order, second-order, and third-order bronchi. A small number of
primary carcinomas of the lung arise in the periphery of the lung substance from the alveolar septal
cells or terminal bronchioles. These are predominantly adenocarcinomas, including those of the
bronchioloalveolar type, to be discussed separately.
Squamous cell carcinoma of the lung begins as an area of in situ cytologic dysplasia that, over an
unknown interval of time, yields a small area of thickening or piling up of bronchial mucosa. With
progression, this small focus, usually less than 1 cm2 in area, assumes the appearance of an
irregular, warty excrescence that elevates or erodes the lining epithelium. The tumor may then
follow a variety of paths. It may continue to fungate into the bronchial lumen to produce an
intraluminal mass. It can also rapidly penetrate the wall of the bronchus to infiltrate along the
peribronchial tissue ( Fig. 15-42 ) into the adjacent region of the carina or mediastinum. In other
instances, the tumor grows along a broad front to produce a cauliflower-like intraparenchymal
mass that appears to push lung substance ahead of it. In almost all patterns, the neoplastic tissue
is gray-white and firm to hard. Especially when the tumors are bulky, focal areas of hemorrhage or
necrosis may appear to produce yellow-white mottling and softening. Sometimes these necrotic
foci cavitate. Often these tumors erode the bronchial epithelium and can be diagnosed by cytologic
examination of sputum, bronchoalveolar lavage fluid, or fine-needle aspiration ( Figs. 15-43A and
B ).

6. Figure 15-42 Lung carcinoma. The gray-white tumor tissue is seen infiltrating the lung
substance. Histologically, this large tumor mass was identified as a squamous cell carcinoma.
Figure 15-43 Cytologic diagnosis of lung cancer is often possible. A, A sputum specimen
shows an orange-staining, keratinized squamous carcinoma cell with a prominent
hyperchromatic nucleus (arrow). B, A fine-needle aspirate of an enlarged lymph node shows
clusters of tumor cells from a small cell carcinoma, with molding and nuclear atypia
characteristic of this tumor (see also Fig. 15-44C ); note the size of the tumor cells compared
with normal polymorphonuclear leukocytes in the left lower corner.
Extension may occur to the pleural surface and then within the pleural cavity or into the pericardium.
Spread to the tracheal, bronchial, and mediastinal nodes can be found in most cases. The

7. frequency of nodal involvement varies slightly with the histologic pattern but averages greater than
50%.
Distant spread of lung carcinoma occurs through both lymphatic and hematogenous pathways.
These tumors have a distressing habit of spreading widely throughout the body and at an early
stage in their evolution except for squamous cell carcinoma, which metastasizes outside the thorax
late. Often the metastasis presents as the first manifestation of the underlying occult pulmonary
lesion. No organ or tissue is spared in the spread of these lesions, but the adrenals, for obscure
reasons, are involved in more than half the cases. The liver (30% to 50%), brain (20%), and bone
(20%) are additional favored sites of metastases.
Squamous Cell Carcinoma.
Squamous cell carcinoma is most commonly found in men and is closely correlated with a
smoking history. Histologically, this tumor is characterized by the presence of keratinization
and/or intercellular bridges. Keratinization may take the form of squamous pearls or individual cells
with markedly eosinophilic dense cytoplasm ( Fig. 15-44A ). These features are prominent in the
well-differentiated tumors, are easily seen but not extensive in moderately differentiated tumors,
and are focally seen in poorly differentiated tumors. Mitotic activity is higher in poorly differentiated
tumors. In the past, most squamous cell carcinomas were seen to arise centrally from the
segmental or subsegmental bronchi. However, the incidence of squamous cell carcinoma of the
peripheral lung is increasing. Squamous metaplasia, epithelial dysplasia, and foci of frank
carcinoma in situ may be seen in bronchial epithelium adjacent to the tumor mass.
Figure 15-44 Histologic appearance of lung carcinoma. A, Well-differentiated squamous cell

8. carcinoma showing keratinization. B, Gland-forming adenocarcinoma. C, Small cell carcinoma
with islands of small deeply basophilic cells and areas of necrosis. D, Large cell carcinoma,
featuring pleomorphic, anaplastic tumor cells and absence of squamous or glandular
differentiation.
Squamous cell carcinomas show the highest frequency of p53 mutations of all histologic types of
lung carcinoma. An influence of p53 status on prognosis has not been demonstrated, except in
very early stages. p53 protein overexpression and, less commonly, mutations may precede
invasion. Abnormal p53 accumulation is reported in 10% to 50% of dysplasias. There is increasing
frequency and intensity of p53 immunostaining with higher-grade dysplasia, and positivity can be
seen in 60% to 90% of squamous cell carcinoma in situ. Loss of protein expression of the tumor
suppressor gene RB is detected by immunohistochemistry in 15% of squamous cell carcinomas.
The CDK-inhibitor p16INK4 is inactivated, and its protein product is lost in 65% of tumors. Multiple
allelic losses are observed in squamous cell carcinomas at locations bearing tumor suppressor
genes. These losses, especially those involving 3p, 9p, and 17p, may precede invasion and be
detected in histologically normal cells in smokers. Overexpression of epidermal growth-factor
receptor has been detected in 80% of squamous cell carcinomas, but it is rarely mutated.
HER-2/neu is highly expressed in 30% of these cancers, but unlike in breast cancer, gene
amplification is not the underlying mechanism.[122]
Adenocarcinoma.
This is a malignant epithelial tumor with glandular differentiation or mucin production by the tumor
cells. Adenocarcinomas show various growth patterns, either pure or, more often, mixed. These
patterns are acinar, papillary, bronchioloalveolar, and solid with mucin formation. Of these, only the
pure bronchioloalveolar carcinoma has distinct gross, microscopic, and clinical features and will be
discussed separately.
Adenocarcinoma is the most common type of lung cancer in women and nonsmokers. As
compared to squamous cell cancers, the lesions are usually more peripherally located, and tend to
be smaller. They vary histologically from well-differentiated tumors with obvious glandular elements
( Fig. 15-44B ) to papillary lesions resembling other papillary carcinomas to solid masses with only
occasional mucin-producing glands and cells. About 80% contain mucin. At the periphery of the
tumor, there is often a bronchioloalveolar pattern of spread (see below). Adenocarcinomas grow
more slowly than squamous cell carcinomas but tend to metastasize widely and earlier. Peripheral
adenocarcinomas are sometimes associated with areas of scarring. Adenocarcinomas, including
bronchioloalveolar carcinomas, are less frequently associated with a history of smoking (still,
greater than 75% are found in smokers) than are squamous or small cell carcinomas (>98%).
K-RAS mutations are seen primarily in adenocarcinoma, with a much lower frequency in
nonsmokers (5%) than in smokers (30%). p53, RB, and p16 mutations and inactivation have the
same frequency in adenocarcinoma as in squamous cell carcinoma.

9. As the name implies, bronchioloalveolar carcinoma occurs in the pulmonary parenchyma in the
terminal bronchioloalveolar regions. It represents, in various series, 1% to 9% of all lung cancers.
Macroscopically, the tumor almost always occurs in the peripheral portions of the lung either as a
single nodule or, more often, as multiple diffuse nodules that sometimes coalesce to produce a
pneumonia-like consolidation. The parenchymal nodules have a mucinous, gray translucence
when secretion is present but otherwise appear as solid, gray-white areas that can be confused
with pneumonia on casual inspection. Because the tumor does not involve major bronchi,
atelectasis and emphysema are infrequent.
Histologically, the tumor is characterized by a pure bronchioloalveolar growth pattern with no
evidence of stromal, vascular, or pleural invasion. The key feature of bronchioloalveolar
carcinomas is their growth along preexisting structures without destruction of alveolar architecture.
This growth pattern has been termed "lepidic," an allusion to the neoplastic cells resembling
butterflies sitting on a fence. It has two subtypes: nonmucinous and mucinous. The former has
columnar, peg-shaped, or cuboidal cells, while the latter has distinctive, tall, columnar cells with
cytoplasmic and intra-alveolar mucin, growing along the alveolar septa ( Fig. 15-45 ).
Ultrastructurally, bronchioloalveolar carcinomas are a heterogeneous group, consisting of
mucin-secreting bronchiolar cells, Clara cells, or, rarely, type II pneumocytes.
Figure 15-45 Bronchioloalveolar carcinoma with characteristic growth along pre-existing
alveolar septa, without invasion. (Courtesy of Dr. Jerome B. Taxy, Department of Pathology,
The University of Chicago, Pritzker School of Medicine, Chicago, IL.)
Nonmucinous bronchioloalveolar carcinomas often consist of a peripheral lung nodule with only
rare aerogenous spread and therefore are amenable to surgical resection. Mucinous
bronchioloalveolar carcinomas, on the other hand, tend to spread aerogenously, forming satellite
tumors. These may present as a solitary nodule or as multiple nodules, or an entire lobe may be
consolidated by tumor, resembling lobar pneumonia. Such lesions are less likely to be cured by
surgery.
Analogous to the adenoma-carcinoma sequence in the colon, it is proposed that adenocarcinoma
of the lung arises from atypical adenomatous hyperplasia progressing to bronchioloalveolar

10. carcinoma, which then transforms into invasive adenocarcinoma. This is supported by the fact that
lesions of atypical adenomatous hyperplasia are monoclonal and they share many molecular
aberrations with invasive adenocarcinomas.[125] Microscopically, atypical adenomatous
hyperplasia is recognized as a well-demarcated focus of epithelial proliferation composed of
cuboidal to low columnar epithelium. These cells demonstrate some cytologic atypia but not to the
extent seen in frank adenocarcinoma. It should be pointed out, however, that not all
adenocarcinomas arise in this manner, nor do all bronchioloalveolar carcinomas become invasive
if left untreated.
Small Cell Carcinoma.
This highly malignant tumor has a distinctive cell type. The epithelial cells are small, with scant
cytoplasm, ill-defined cell borders, finely granular nuclear chromatin (salt and pepper pattern), and
absent or inconspicuous nucleoli ( Fig. 15-44C ). The cells are round, oval, and spindle-shaped,
and nuclear molding is prominent. There is no absolute size for the tumor cells, but in general, they
are smaller than small resting lymphocytes. The mitotic count is high. The cells grow in clusters
that exhibit neither glandular nor squamous organization. Necrosis is common and often extensive.
Basophilic staining of vascular walls due to encrustation by DNA from necrotic tumor cells is
frequently present. Grading is inappropriate, since all small cell carcinomas are high grade. A
single variant of small cell carcinoma is recognized: combined small cell carcinoma, in which there
is a mixture of small cell carcinoma and any other non-small cell component, including large cell
neuroendocrine carcinoma and sarcoma.
Electron microscopy shows dense-core neurosecretory granules 100 nm in diameter in two thirds
of cases. The granules are similar to those found in the neuroendocrine argentaffin (Kulchitsky)
cells present along the bronchial epithelium, particularly in the fetus and neonate. Although
distinctive, electron microscopy is not needed for routine diagnosis. The occurrence of
neurosecretory granules, the ability of some of these tumors to secrete polypeptide hormones, and
the presence (ascertained by immunohistochemical stains) of neuroendocrine markers such as
chromogranin, synaptophysin, and Leu-7 (in 75% of cases) and parathormone-like and other
hormonally active products suggest derivation of this tumor from neuroendocrine progenitor cells of
the lining bronchial epithelium. They are the most common pattern associated with ectopic
hormone production (discussed later).
Small cell carcinomas have a strong relationship to cigarette smoking; only about 1% occur in
nonsmokers. They occur both in major bronchi and in the periphery of the lung. There is no known
preinvasive phase or carcinoma in situ. They are the most aggressive of lung tumors, metastasize
widely, and are virtually incurable by surgical means.
p53 and RB tumor suppressor genes are frequently mutated (50% to 80% and 80% to 100% of
small cell carcinomas, respectively). Immunohistochemistry demonstrates intense expression of
the anti-apoptotic gene BCL2 in 90% of tumors, in contrast with a low frequency of expression of
the pro-apoptotic gene BAX.
Large Cell Carcinoma.

11. This is an undifferentiated malignant epithelial tumor that lacks the cytologic features of small cell
carcinoma and glandular or squamous differentiation. The cells typically have large nuclei,
prominent nucleoli, and a moderate amount of cytoplasm ( Fig. 15-44D ). Large cell carcinomas
probably represent squamous cell carcinomas and adenocarcinomas that are so undifferentiated
that they can no longer be recognized by light microscopy. Ultrastructurally, however, minimal
glandular or squamous differentiation is common. One histologic variant is large cell
neuroendocrine carcinoma. This is recognized by such features as organoid nesting, trabecular,
rosette-like and palisading patterns. These features suggest neuroendocrine differentiation, which
can be confirmed by immunohistochemistry or electron microscopy. This tumor has the same
molecular changes as small cell carcinoma.
Combined Carcinoma.
Approximately 10% of all lung carcinomas have a combined histology, including two or more of the
above types.
Secondary Pathology.
Lung carcinomas cause related anatomic changes in the lung substance distal to the point of
bronchial involvement. Partial obstruction may cause marked focal emphysema; total
obstruction may lead to atelectasis. The impaired drainage of the airways is a common cause
for severe suppurative or ulcerative bronchitis or bronchiectasis. Pulmonary abscesses
sometimes call attention to a silent carcinoma that has initiated the chronic suppuration.
Compression or invasion of the superior vena cava can cause venous congestion, dusky head and
arm edema, and, ultimately, circulatory compromise—the superior vena cava syndrome.
Extension to the pericardial or pleural sacs may cause pericarditis ( Chapter 12 ) or pleuritis with
significant effusions.
Staging.
A uniform TNM system for staging cancer according to its anatomic extent at the time of diagnosis
is extremely useful for many reasons, chiefly for comparing treatment results from different centers.
The staging system in current use[126] is presented in Table 15-11 .
Table 15-11 -- New International Staging System for Lung Cancer
T1 Tumor <3 cm without pleural or main stem bronchus involvement
Tumor >3 cm or involvement of main stem bronchus 2 cm from carina, visceral
T2
pleural involvement, or lobar atelectasis
Tumor with involvement of chest wall (including superior sulcus tumors),
T3 diaphragm, mediastinal pleura, pericardium, main stem bronchus 2 cm from
carina, or entire lung atelectasis
Tumor with invasion of mediastinum, heart, great vessels, trachea, esophagus,
T4
vertebral body, or carina or with a malignant pleural effusion

12. N0 No demonstrable metastasis to regional lymph nodes
N1 Ipsilateral hilar or peribronchial nodal involvement
N2 Metastasis to ipsilateral mediastinal or subcarinal lymph nodes
Metastasis to contralateral mediastinal or hilar lymph nodes, ipsilateral or
N3
contralateral scalene, or supraclavicular lymph nodes
M0 No (known) distant metastasis
M1 Distant metastasis present
Stage Grouping
Stage Ia T1 N0 M0
Stage Ib T2 N0 M0
Stage IIa T1 N1 M0
Stage IIb T2 N1 M0
T3 N0 M0
Stage IIIa T1–3 N2 M0
T3 N1 M0
Stage IIIb Any T N3 M0
T3 N2 M0
T4 Any N M0
Stage IV Any T Any N M1
Adapted from Mountain C: Revisions in the International System for Staging Lung Cancer. Chest
111:1710, 1997.
Clinical Course.
Lung cancer is one of the most insidious and aggressive neoplasms in the whole realm of oncology.
In the usual case, it is discovered in patients in their fifties whose symptoms are of several months'
duration. The major presenting complaints are cough (75%), weight loss (40%), chest pain (40%),
and dyspnea (20%). Some of the more common local manifestations of lung cancer and their
pathologic bases are listed in Table 15-12 . Not infrequently, the tumor is discovered by its
secondary spread during the course of investigation of an apparent primary neoplasm elsewhere.
Bronchioloalveolar carcinomas, by definition, are noninvasive tumors and do not metastasize;
rather, they kill by suffocation.
Table 15-12 -- Local Effects of Lung Tumor Spread
Clinical Feature Pathologic Basis

13. Clinical Feature Pathologic Basis
Pneumonia, abscess, lobar
Tumor obstruction of airway
collapse
Tumor obstruction; accumulation of cellular lipid in foamy
Lipid pneumonia
macrophages
Pleural effusion Tumor spread into pleura
Hoarseness Recurrent laryngeal nerve invasion
Dysphagia Esophageal invasion
Diaphragm paralysis Phrenic nerve invasion
Rib destruction Chest wall invasion
SVC syndrome SVC compression by tumor
Horner syndrome Sympathetic ganglia invasion
Pericarditis, tamponade Pericardial involvement
SVC, superior vena cava.
The outlook is poor for most patients with lung carcinoma. Despite all efforts at early diagnosis by
frequent radioscopic examination of the chest, cytologic examination of sputum, and bronchial
washings or brushings and the many improvements in thoracic surgery, radiotherapy, and
chemotherapy, the overall 5-year survival rate is on the order of 15%. In many large clinics, not
more than 20% to 30% of lung cancer patients have lesions sufficiently localized to permit even an
attempt at resection. In general, the adenocarcinoma and squamous cell patterns tend to remain
localized longer and have a slightly better prognosis than do the undifferentiated cancers, which
usually are advanced lesions by the time they are discovered. The survival rate is 48% for cases
detected when the disease is still localized. Only 15% of lung cancers are diagnosed at this early
stage. Surgical resection for small cell carcinoma is so ineffective that the diagnosis essentially
precludes surgery. Untreated, the survival time for patients with small cell cancer is 6 to 17 weeks.
This cancer is particularly sensitive to radiation and chemotherapy, and potential cure rates of 15%
to 25% for limited disease have been reported in some centers. Most patients have distant
metastases on diagnosis. Thus, even with treatment, the mean survival after diagnosis is about 1
year.
Despite this discouraging outlook, some patients have been cured by lobectomy or
pneumonectomy, emphasizing the continued need for early diagnosis and adequate prompt
therapy.
Paraneoplastic Syndromes.

14. Lung carcinoma can be associated with a number of paraneoplastic syndromes[127] ( Chapter 7 ),
some of which may antedate the development of a gross pulmonary lesion. The hormones or
hormone-like factors elaborated include
? Antidiuretic hormone (ADH), inducing hyponatremia owing to inappropriate ADH secretion
? Adrenocorticotropic hormone (ACTH), producing Cushing syndrome
? Parathormone, parathyroid hormone-related peptide, prostaglandin E, and some cytokines, all
implicated in the hypercalcemia often seen with lung cancer
? Calcitonin, causing hypocalcemia
? Gonadotropins, causing gynecomastia
? Serotonin and bradykinin, associated with the carcinoid syndrome
The incidence of clinically significant syndromes related to these factors ranges from 1% to 10% of
all lung cancer patients, although a much higher proportion of patients show elevated serum levels
of these (and other) peptide hormones. Any one of the histologic types of tumors may occasionally
produce any one of the hormones, but tumors that produce ACTH and ADH are predominantly
small cell carcinomas, whereas those that produce hypercalcemia are mostly squamous cell
tumors. The carcinoid syndrome is more common with the carcinoid tumor, described later, and is
only rarely associated with small cell carcinoma. However, small cell carcinoma occurs much more
commonly; therefore, one is much more likely to encounter carcinoid syndrome in these patients.
Other systemic manifestations of lung carcinoma include the Lambert-Eaton myasthenic syndrome
( Chapter 27 ), in which muscle weakness is caused by auto-antibodies (possibly elicited by tumor
ionic channels) directed to the neuronal calcium channel;[127] peripheral neuropathy, usually purely
sensory; dermatologic abnormalities, including acanthosis nigricans ( Chapter 25 ); hematologic
abnormalities, such as leukemoid reactions; and finally, a peculiar abnormality of connective tissue
called hypertrophic pulmonary osteoarthropathy, associated with clubbing of the fingers.
Apical lung cancers in the superior pulmonary sulcus tend to invade the neural structures around
the trachea, including the cervical sympathetic plexus, and produce a group of clinical findings that
includes severe pain in the distribution of the ulnar nerve and Horner syndrome (enophthalmos,
ptosis, miosis, and anhidrosis) on the same side as the lesion. Such tumors are also referred to as
Pancoast tumors.
NEUROENDOCRINE PROLIFERATIONS AND TUMORS
Neuroendocrine lesions share morphologic and biochemical features with cells of the dispersed
neuroendocrine cell system ( Chapter 24 ).[128] The normal lung contains neuroendocrine cells within
the epithelium as single cells or as clusters, the neuroepithelial bodies. While virtually all pulmonary
neuroendocrine cell hyperplasias are secondary to airway fibrosis and/or inflammation, a rare
disorder called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia appears to be a
precursor to the development of multiple tumorlets and typical or atypical carcinoids.

15. Neoplasms of neuroendocrine cells in the lung include benign tumorlets, small, inconsequential
hyperplastic neuroendocrine cells seen in areas of scarring or chronic inflammation; carcinoids;
and the (already discussed) highly aggressive small cell carcinoma and large cell neuroendocrine
carcinoma of the lung. Although neuroendocrine tumors share certain morphologic, ultrastructural,
molecular genetic, and immunohistochemical characteristics, they are classified separately, since
there are significant differences between them in incidence, clinical, epidemiologic, histologic,
survival, and molecular characteristics. For example, in contrast to small cell and large cell
neuroendocrine carcinomas, both typical and atypical carcinoids can occur in patients with multiple
endocrine neoplasia type I. Also note that neuroendocrine differentiation can be demonstrated by
immunohistochemistry in 10% to 20% of lung carcinomas that do not show neuroendocrine
morphology by light microscopy, the clinical significance of which is uncertain.
Carcinoid Tumors.
Carcinoid tumors represent 1% to 5% of all lung tumors. Most patients with these tumors are
younger than 40 years of age, and the incidence is equal for both sexes. Approximately 20% to
40% of patients are nonsmokers. Carcinoid tumors are low-grade malignant epithelial neoplasms
that are subclassified into typical and atypical carcinoids on the basis of morphologic criteria
described below. Typical carcinoids have no p53 mutations or BCL2/BAX imbalance, while atypical
carcinoids show these changes in 20% to 40% and 10% to 20% of tumors, respectively. Some
carcinoids also show loss of heterozygosty at 3p, 13q14 (RB), 9p, and 5q22, which are found in all
neuroendocrine tumors with increasing frequency from typical to atypical carcinoid to large cell
neuroendocrine and small cell carcinoma.
Morphology.
Carcinoids may arise centrally or may be peripheral. On gross examination, the central tumors
grow as finger-like or spherical polypoid masses that commonly project into the lumen of the
bronchus and are usually covered by an intact mucosa ( Fig. 15-46A ). They rarely exceed 3 to 4
cm in diameter. Most are confined to the main stem bronchi. Others, however, produce little
intraluminal mass but instead penetrate the bronchial wall to fan out in the peribronchial tissue,
producing the so-called collarbutton lesion. Peripheral tumors are solid and nodular. Spread to
local lymph nodes at the time of resection is more likely with atypical carcinoid.

16. Figure 15-46 A, Bronchial carcinoid growing as a spherical, pale mass (arrow) protruding into
the lumen of the bronchus. B, Histologic appearance of bronchial carcinoid, demonstrating
small, rounded, uniform cells.
Histologically, the tumor is composed of organoid, trabecular, palisading, ribbon, or rosette-like
arrangements of cells separated by a delicate fibrovascular stroma. In common with the lesions of
the gastrointestinal tract, the individual cells are quite regular and have uniform round nuclei and a
moderate amount of eosinophilic cytoplasm ( Fig. 15-46B ). On electron microscopy, the cells
exhibit the dense-core granules characteristic of other neuroendocrine tumors and, by
immunochemistry, are found to contain serotonin, neuron-specific enolase, bombesin, calcitonin,
or other peptides. Typical carcinoids have fewer than two mitoses per 10 high-power fields and
lack necrosis, while atypical carcinoids have between two and 10 mitoses per 10 high-power fields
and/or foci of necrosis.[129] The atypical carcinoids tend to show more cellular atypia, increased
cellularity, nucleoli, lymphatic invasion, and disorganized architecture.
Clinical Features.
The clinical manifestations of bronchial carcinoids emanate from their intraluminal growth, their
capacity to metastasize, and the ability of some of the lesions to elaborate vasoactive amines.
Persistent cough, hemoptysis, impairment of drainage of respiratory passages with secondary
infections, bronchiectasis, emphysema, and atelectasis all are byproducts of the intraluminal
growth of these lesions.
Most interesting, albeit rare, are functioning lesions capable of producing the classic carcinoid
syndrome, that is, intermittent attacks of diarrhea, flushing, and cyanosis. Overall, most bronchial
carcinoids do not have secretory activity and do not metastasize to distant sites but follow a
relatively benign course for long periods and are therefore amenable to resection. The reported 5-
to 10-year survival rates are 87% and 87% for typical carcinoids, 56% and 35% for atypical
carcinoids, 27% and 9% for large cell neuroendocrine carcinoma, and 9% and 5% for small cell
carcinoma, respectively.[129]
MISCELLANEOUS TUMORS
Lesions of the complex category of benign and malignant mesenchymal tumors, such as
inflammatory myofibroblastic tumor, fibroma, fibrosarcoma, lymphangioleiomyomatosis,
leiomyoma, leiomyosarcoma, lipoma, hemangioma, hemangiopericytoma, and chondroma, may
occur but are rare. Benign and malignant hematopoeitic tumors, similar to those described in other
organs, may also affect the lung, either as isolated lesions or, more commonly, as part of a
generalized disorder. These include Langerhans cell histiocytosis, non-Hodgkin and Hodgkin
lymphomas, lymphomatoid granulomatosis (which are diffuse large B-cell and T-cell lymphomas),
and low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue.

17. A lung hamartoma is a relatively common lesion that is usually discovered as an incidental,
rounded focus of radio-opacity (coin lesion) on a routine chest film. The majority of the tumors are
peripheral, solitary, less than 3 to 4 cm in diameter, and well circumscribed. Pulmonary hamartoma
consists of nodules of connective tissue intersected by epithelial clefts. Cartilage is the most
common connective tissue, but there may also be cellular fibrous tissue and fat. The epithelial
clefts are lined by ciliated columnar epithelium or nonciliated epithelium and probably represent
entrapment of respiratory epithelium. The traditional term "hamartoma" is retained for this lesion,
but several features suggest that it is a neoplasm rather than a congenital lesion, such as its rarity
in childhood, its increasing incidence with age, and the finding of chromosomal aberrations
involving either 6p21 or 12q14-15, indicating a clonal origin.[115]
Inflammatory myofibroblastic tumor, although rare, is more common in children, with an equal male
to female ratio. Presenting symptoms include fever, cough, chest pain, and hemoptysis. It may also
be asymptomatic. Imaging studies show a single (rarely multiple) round, well-defined, usually
peripheral mass with calcium deposits in about a quarter of cases. Grossly, the lesion is firm, 3 to
10 cm in diameter, and grayish white. Microscopically, there is proliferation of spindle-shaped
fibroblasts and myofibroblasts, lymphocytes, plasma cells, and peripheral fibrosis. Clonal
chromosomal aberrations have been demonstrated in a number of these tumors, indicating that
these are neoplastic proliferations.
Tumors in the mediastinum either may arise in mediastinal structures or may be metastatic from
the lung or other organs. They may also invade or compress the lungs. Table 15-13 lists the most
common tumors in the various compartments of the mediastinum. Specific tumor types are
discussed in appropriate sections of this book.
Table 15-13 -- Mediastinal Tumors and Other Masses
Superior Mediastinum
Lymphoma
Thymoma
Thyroid lesions
Metastatic carcinoma
Parathyroid tumors
Anterior Mediastinum
Thymoma
Teratoma
Lymphoma
Thyroid lesions
Parathyroid tumors
Posterior Mediastinum

18. Neurogenic tumors (schwannoma, neurofibroma)
Lymphoma
Gastroenteric hernia
Middle Mediastinum
Bronchogenic cyst
Pericardial cyst
Lymphoma
METASTATIC TUMORS
The lung is the most common site of metastatic neoplasms. Both carcinomas and sarcomas arising
anywhere in the body may spread to the lungs via the blood or lymphatics or by direct continuity.
Growth of contiguous tumors into the lungs occurs most often with esophageal carcinomas and
mediastinal lymphomas.
Morphology.
The pattern of metastatic growth within the lungs is quite variable. In the usual case, multiple
discrete nodules (cannonball lesions) are scattered throughout all lobes ( Fig. 15-47 ). These
discrete lesions tend to occur in the periphery of the lung rather than in the central locations of the
primary lung carcinoma. Other patterns include solitary nodule, endobronchial, pleural, pneumonic
consolidation, and mixtures of the above. Foci of lepidic growth similar to bronchioloalveolar
carcinoma are seen occasionally with metastatic carcinomas and may be associated with any of
the patterns listed above.
Figure 15-47 Numerous metastases from a renal cell carcinoma. (Courtesy of Dr. Michelle
Mantel, Brigham and Women's Hospital, Boston, MA.)

19. Metastatic growth may be confined to peribronchiolar and perivascular tissue spaces, presumably
when the tumor has extended to the lung through the lymphatics. In these cases, the lung septa
and connective tissue are diffusely infiltrated with the gray-white tumor. The subpleural lymphatics
may be outlined by the contained tumor, producing a gross appearance referred to as lymphangitis
carcinomatosa. Least commonly, the metastatic tumor is not apparent on gross examination and
becomes evident only on histologic section as a diffuse intralymphatic dissemination dispersed
throughout the peribronchial and perivascular channels. In certain instances, microscopic tumor
emboli fill the small pulmonary vessels and may result in life-threatening pulmonary hypertension
or hemorrhage and hemoptysis.
(From:
http://www.mdconsult.com/das/book/body/105692340-2/0/1249/149.html?tocnode=51156242&fromURL
=149.html#4-u1.0-B0-7216-0187-1..50019-5--cesec186_1967)