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.

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.

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

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

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 ).

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

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

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.

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

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.

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

T2 Tumor >3 cm or involvement of main stem bronchus 2 cm from carina, visceral

pleural involvement, or lobar atelectasis

T3

Tumor with involvement of chest wall (including superior sulcus tumors),

diaphragm, mediastinal pleura, pericardium, main stem bronchus 2 cm from

carina, or entire lung atelectasis

T4 Tumor with invasion of mediastinum, heart, great vessels, trachea, esophagus,

vertebral body, or carina or with a malignant pleural effusion

N0 No demonstrable metastasis to regional lymph nodes

N1 Ipsilateral hilar or peribronchial nodal involvement

N2 Metastasis to ipsilateral mediastinal or subcarinal lymph nodes

N3 Metastasis to contralateral mediastinal or hilar lymph nodes, ipsilateral or

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

Clinical Feature Pathologic Basis

Pneumonia, abscess, lobar

collapse Tumor obstruction of airway

Lipid pneumonia Tumor obstruction; accumulation of cellular lipid in foamy

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.

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.

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.

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.

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

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.)

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.

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