Chapter 15:Lung:Tumors

Question 1

Most 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.

Question 2

Etiology of lung cancer

Answer 2

• Tobacco Smoking.
• Industrial Hazards.
• Air Pollution
• Molecular Genetics
• Precursor Lesions.

Question 3

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

Answer 3

• (1) the amount of daily smoking,
• (2) the tendency to inhale, and
• (3) the duration of the smoking habit.

Question 4

Compared with
nonsmokers, average smokers of cigarettes have a tenfold greater risk of developing lung
cancer, andheavy smokers (more than 40 cigarettes per day for several years)have a60-fold
greater risk.

Question 5

Women have a higher susceptibility to tobacco carcinogens than men do.

T or F

Answer 5

True

Question 6

Cessation of smoking for 10 years reduces risk but never to control levels.

It should be noted,
however, that despite compelling evidence supporting the role of cigarette smoking, only 11% of
heavy smokers develop lung cancer in their lifetime.

Clearly, there are other (genetic) factors
involved as will be discussed later.

Question 7

Epidemiologic studies also show an association between
cigarette smoking and carcinoma of the mouth, pharynx, larynx, esophagus, pancreas, uterine
cervix, kidney, and urinary bladder.

Question 8

Secondhand smoke, or environmental tobacco smoke,
contains numerous human carcinogens for which there is no safe level of exposure.

It is
estimated that each year about 3000 nonsmoking adults die of lung cancer as a result of
breathing secondhand smoke.

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.

Question 9

Lung tumors of smokers frequently contain a typical, though not specific, molecular
fingerprint in the form of G : C > T : A mutations in the p53 gene that are probably caused by
benzo[a]pyrene, one of the many carcinogens in tobacco smoke

Question 10

More than 1200 substances have been counted in
cigarette smoke, many of which are potential carcinogens.

They include both initiators
______________

Answer 10

(polycyclic aromatic hydrocarbons such as benzo[a]pyrene)

Question 11

More than 1200 substances have been counted in
cigarette smoke, many of which are potential carcinogens.

They include promoters, such as__________.

Answer 11

phenol
derivatives

Radioactive elements may also be found (polonium-210, carbon-14, and
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

Question 12

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 four times higher than those in the general
population, and among smoking miners they are about 10 times higher.

Question 13

The risk of lung cancer is increased with asbestos.

Lung cancer is the most frequent
malignancy in individuals exposed to asbestos, particularly when coupled with smoking. [80]
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.

Question 14

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. [142,] [143]

Radon is a ubiquitous radioactive gas that has been linked epidemiologically
to increased lung cancer in miners exposed to relatively high concentrations.

The pathogenic
mechanism is believed to be _______________-

Answer 14

inhalation and bronchial deposition of radioactive decay products
that become attached to environmental aerosols. These data have generated concern that lowlevel
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 )

Question 15

lung cancers can be divided into two clinical subgroups:

Answer 15

1. small cell carcinoma and
2. non-small cell carcinoma

Some molecular lesions
are common to both types, whereas others are relatively specific.

Question 16

The dominant oncogenes that
are frequently involved in lung cancer include:

Answer 16

c-MYC, KRAS, EGFR, c-MET , and c-KIT .

Question 17

The commonly deleted or inactivated tumor suppressor genes in lung cancer include :

Answer 17

p53, RB1, p16(INK4a), and
multiple loci on chromosome 3p

Question 18

At this locale there are numerous candidate tumor suppressor genes in lung cancer, such as FHIT , RASSF1A, and others that remain to be identified

Question 19

Of the various cancer associated genes:

are most commonly involved in small cell lung carcinoma

Answer 19

• C-KIT (40–70%),
• MYCN and MYCL (20–30%),
• p53 (90%)
• , 3p (100%),
• RB (90%), and
• BCL2 (75–90%)

Question 20

By
comparison, _________ are the ones most
commonly affected in non-small cell lung carcinoma.

Answer 20

• EGFR (25%),
• KRAS (10–15%),
• p53 (50%),
• p16 INK4a (70%)

Question 21

It should be noted that C-KIT is over
expressed but only rarely mutated. Hence, drugs that target its tyrosine kinase domain (such as
imatinib) are ineffective. Recall that in tumors with mutation of that kinase domain (e.g.,
gastrointestinal stromal tumor) this drug is useful for treatment. Telomerase activity is increased
in over 80% of lung tumor tissues.

Question 22

There are several signal transduction molecules that are activated in lung cancer, such as AKT,
phosphatidylinositol-3-kinase, ERK1/2, STAT5, and focal adhesion proteins such as paxillin.

Although certain genetic changes are known to be early (inactivation of chromosome 3p
suppressor genes) or late (activation of KRAS), 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 individuals 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”). [147]

On this fertile soil,
the cells that accumulate additional mutations ultimately develop into cancer.

Question 23

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 ). [148

] 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.In addition, large scale linkage studies point to an autosomal susceptibility locus on
6q23-25. More recently, genome-wide association studies have revealed an intriguing link to
polymorphisms in the nicotine acetylcholine receptor gene located on chromosome 15q25 and
lung cancer in both smokers and nonsmokers

Question 24

It should also be pointed out that 25% of lung cancers worldwide arise in nonsmokers and these
are pathogenetically distinct.

They occur more commonly in:

Answer 24

• women, and most are
• adenocarcinomas.
• They tend to have EGFR mutations, almost never have KRAS mutations and p53 mutations, although common, occur less commonly.
• The nature of the p53 mutations are also distinct. [150]

Question 25

Tumor classification is important for consistency in patient treatment and because it provides a
basis for epidemiologic and biologic studies.

The most recent classification of the World Health Organization [138] 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 [151] :

Answer 25

• Adenocarcinoma (males 37%, females 47%)
• Squamous cell carcinoma (males 32%, females 25%)
• Small cell carcinoma (males 14%, females 18%)
• Large cell carcinoma (males 18%, females 10%)

Question 26

TABLE 15-10 – Histologic Classification of Malignant Epithelial Lung Tumors

Answer 26

• 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

Question 27

The incidence of ____________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. [152]

Answer 27

adenocarcinoma

The
basis for this change is unclear.

A possible factor is the increase in women smokers, but thisnonly highlights our lack of knowledge about why women tend to develop 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

Question 28

There may be mixtures of histologic patterns, even in the same cancer.

T or F

Answer 28

True

Thus, combined types
of squamous cell carcinoma and adenocarcinoma or of small-cell and squamous cell carcinoma
occur in about 10% of patients

Question 29

. 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:

Answer 29

• small cell carcinomas (almost always metastatic, high initial​ response to chemotherapy) versus
• non-small cell carcinomas (less often metastatic, less responsive).

Question 30

The strongest relationship to smoking is with _______________

Answer 30

squamous cell and small cell

carcinoma.

Question 31

Lung carcinomas arise most often in and about the _______

Answer 31

hilus of the lung.

About
three fourths of the lesions take their origin from first-order, second-order, and third-order
bronchi.

Question 32

An increasing number of primary carcinomas of the lung arise in the periphery of the
lung from the alveolar septal cells or terminal bronchioles. These are predominantly what type of lung cancer?

Answer 32

adenocarcinomas, including those of the bronchioloalveolar type, to be discussed separately

Question 33

The preneoplastic lesions that antedate, and usually accompany, invasive squamous cell
carcinoma are well characterized.

Squamous cell carcinomas are often preceded for years by squamous metaplasia or dysplasia in the bronchial epithelium, which then transforms to
carcinoma in situ,a phase thatmay last for several years

by

Answer 33

By this time,
atypical cells may be identified in cytologic smears of sputum or in bronchial lavage fluids or
brushings, although the lesion is asymptomatic and undetectable on radiographs

Question 34

Eventually,
the growing neoplasm reaches a symptomatic stage, when a well-defined tumor mass begins
to obstruct the lumen of a major bronchus,oftenproducing distal atelectasis and infection.

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. 15-41 ) 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.

Question 35

In almost all patterns the neoplastic tissue is gray-white and firm to hard.

T or F

Answer 35

True

Especially when the
tumors are bulky, focal areas of hemorrhage or necrosis may appear to produce red or
yellow-white mottling and softening.

Sometimes these necrotic foci cavitate.

Often these
tumors erode the bronchial epitheliumandcan be diagnosed by cytologic examination of
sputum, bronchoalveolar lavage fluid, or fine-needle aspiration (

Question 36

In lung cancer, 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%.

Question 37

What is Adenocarcinoma?

Answer 37

Adenocarcinoma.

This is a malignant epithelial tumor with glandular differentiation or mucin
production by the tumor cells.

Question 38

Adenocarcinomas

Answer 38

grow in various patterns, including :

• acinar,
• papillary,
• bronchioloalveolar,
• and solid with mucin formation.

Question 39

Of the types of pattern of adenocarcinoma, only pure

______________has distinct gross, microscopic, and clinical features and will be
discussed separately

Answer 39

bronchioloalveolar carcinoma

Question 40

What type of lung cancer is the most common type of lung cancer in women and nonsmokers

Answer 40

Adenocarcinoma is the most common type of lung cancer in women and nonsmokers

Question 41

As compared with squamous cell cancers, the lesions of adenocarcinoma are usually more _________

Answer 41

peripherally located, and
tend to be smaller.

Question 42

Adenocarcinoma vary histologicall from what?

Answer 42

They vary histologically from well-differentiated tumors with obvious

• *glandular elements** ( Fig. 15-43A ) to papillary lesions resembling other papillary carcinomas
• *to solid masses with only occasional mucin-producing glands and cell**s.

Question 43

In adenocarcinoma the majority are
positive for___________.

Answer 43

thyroid transcription factor-1 (TTF-1) and about 80% contain mucin

Question 44

In adenocarcinoma at the
periphery of the tumor there is often a _________

Answer 44

bronchioloalveolar pattern of spread (see below).

Question 45

Adenocarcinomas grow more slowly than squamous cell carcinomas but tend to metastasize
widely and earlier.

T or F

Answer 45

True

Question 46

What pattern of Adenocarcinoma has a better outcome than invasive carinomas of the same size?

Answer 46

Peripheral adenocarcinomas with a small central invasive component associated with scarring and a predominantly peripheral bronchioloalveolar growth pattern may have a better outcome than invasive carcinomas of the same size.

Question 47

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% in smokers).

Question 48

What mutation occur primarily in adenocarcinoma?

Answer 48

**KRAS mutations** occur primarily in adenocarcinoma, and are seen at a much lower frequency
in nonsmokers (5%) than in smokers (30%).

Question 49

What mutations and inactivation in adenocarcinoma have the same frequency un sq cell carcinoma?

Answer 49

p53, RB1, and p16 mutations and inactivation
have the same frequency in adenocarcinoma as in squamous cell carcinoma.

Question 50

What mutation and amplification in the __________ occur in patients with
adenocarcinoma (mostly women, nonsmokers, and those of Asian origin). [154]

Answer 50

Mutations and amplifications in the epidermal growth factor receptor gene (EGFR) occur in patients with
adenocarcinoma (mostly women, nonsmokers, and those of Asian origin). [154]

A prospective
trial has demonstrated that patients with EGFR mutations have improved survival with upfront
EGFR inhibitor treatment.

KRAS mutations highly correlate with worse outcome and resistance to EGFR inhibitors. [154]

Also, c-MET can be amplified or mutated in lung cancer, for which targeted therapies are being developed

Question 51

What is bronchioalveolar carcinoma?

Answer 51

bronchioloalveolar carcinoma occurs in the pulmonary parenchyma in the terminal bronchioloalveolar regions.

It represents, in various series, 1% to 9% of all
lung cancers

.

Question 52

In bronchioalveolar carcinoma macroscopically, the tumor almost always occurs in the ________.

Answer 52

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, graywhite
areas that can be confused with pneumonia on gross inspection.

Question 53

What is the histological appearance of the tumor of bronchioalveolar ca?

Answer 53

​Histologically, the tumor is characterized by a pure bronchioloalveolar growth pattern with no
evidence of stromal, vascular, or pleural invasion.

Question 54

The key feature of bronchioloalveolar
carcinomas_____________

Answer 54

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.

Question 55

What are the two subtypes of lepidic growth?

Answer 55

It has two subtypes: nonmucinous and mucinous.

Question 56

What is the appearance of nonmucinous pattern?

Answer 56

The former has columnar, peg-shaped, or cuboidal cells.

Question 57

What is the appearance of the mucinous growth?

Answer 57

while the latter has distinctive, tall,
columnar cells with cytoplasmic and intra-alveolar mucin, growing along the alveolar septa (
Fig. 15-44 ).

Question 58

Ultrastructurally, bronchioloalveolar carcinomas are a heterogeneous group,
consisting of :

Answer 58

• mucin-secreting bronchiolar cells,
• Clara cells,(are a group of cells, sometimes called “nonciliated bronchiolar secretory cells”, found in the bronchiolar epithelium of mammals including man) or,
• rarely, type II pneumocytes.

Question 59

Nonmucinous bronchioloalveolar carcinomas often ____________

Answer 59

consist of a peripheral lung nodule with
only rare aerogenous spread and therefore are amenable to surgical resection with an
excellent 5-year survival.

Question 60

Mucinous bronchioloalveolar carcinomas, on the other hand, tend to
:

Answer 60

• 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 and thus are less likely to be cured by surgery

Question 61

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 thentransforms into invasive adenocarcinoma.

This is supported by :

Answer 61

This is supported by the observation that lesions of atypical adenomatous hyperplasia are

• *monoclonal and they share many molecular aberrations such as EGFR mutations** with
• *nonmucinous bronchioloalveolar carcinomas** and with invasive adenocarcinomas. [156]

Question 62

Microscopically, atypical adenomatous hyperplasia is recognized as a :

Answer 62

well-demarcated focus
of epithelial proliferation composed of cuboidal to low columnar epithelium ( Fig. 15-45 ).
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

Question 63

What is Squamous Cell Carcinoma?

Answer 63

. Squamous cell carcinoma is most commonly found in men and
is closely correlated with a smoking history.

Question 64

What is the characteristic of Squamous cells carcinoma histologically?

Answer 64

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 (see Fig. 15-
43B ).

These features are prominent in the well-differentiated tumors, are easily seen but not
extensive in moderately differentiated tumors,andare 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 (see Fig. 15-40 ).

Question 65

What type of lung carcinoma shows the highest frequency of p53 mutatations?

Answer 65

Squamous cell carcinomas show the highest frequency of p53 mutations of all histologic types of lung carcinoma. 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 RB1 is detected by immunohistochemistry in 15% of
squamous cell carcinomas. The cyclin-dependent kinase inhibitor p16(INK4a) 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 EGFR 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

Question 66

What is small cell carcinoma?

Answer 66

Small Cell Carcinoma .

This highly malignant tumor has a distinctive cell type.

• The epithelial​ cells are relatively small, with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin (salt and pepper pattern), and absent or inconspicuous nucleoli (see Fig. 15-43C ).
• The cells are round, oval, or spindle-shaped, and nuclear molding is prominent.
• There is no​ absolute size for the tumor cells, but in general they are smaller than three 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 (Azzopardi effect) is frequently present

.” SMALL BUT TERRIBLE”

Question 67

What is Azzopardi effect?

Answer 67

Basophilic staining of
vascular walls due to encrustation by DNA from necrotic tumor cells (Azzopardi effect)

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

Question 68

All small cell carcinomas are high grade.

T or F

Answer 68

True

Question 69

A single variant of small cell
carcinoma is recognized:

Answer 69

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.

Question 70

What is the electron microscopic appearanc of small cell carcinoma?

Answer 70

Electron microscopy shows dense-core neurosecretory granules, about 100 nm in diameter,
in two thirds of cases.

The granules are similar to those found in the neuroendocrine cells
present along the bronchial epithelium, particularly in the fetus and neonate.

Though
distinctive, electron microscopy is not needed for diagnosis.

The occurrence of
neurosecretory granules, the ability of some of these tumors to secrete polypeptide
hormones, and the presence of neuroendocrine markers such as chromogranin,
synaptophysin, and CD57 (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.

Question 71

This lung cancer type is most commonly associated with ectopic
hormone production (discussed later).

Answer 71

Small cell carcinoma

Question 72

Small cell carcinomas have a strong relationship to cigarette smoking

T or F

Answer 72

True

; only about 1% occur in
nonsmokers.

They may arise in major bronchi or in the periphery of the lung.

Question 73

Small cell carcinoma has a preinvasive phase or carcinoma in situ.

T or F

Answer 73

False

• *There is no**
• *known preinvasive phase or carcinoma in sit**u.

They are the most aggressive of lung tumors,
metastasize widely, and are virtually incurable by surgical means

SMALL BUT TERRIBLE

Like me! ; )

Question 74

What is most commonly mutated in Small cell carcinoma?

Answer 74

p53 and RB1 tumor suppressor genes are frequently mutated (50% to 80% and 80% to 100%
of small cell carcinomas, respectively).

Immunohistochemistry demonstrates high levels of the
anti-apoptotic protein BCL2 in 90% of tumors, in contrast with a low frequency of expression
of the pro-apoptotic protein BAX.

Question 75

What is Large Cell Carcinoma?

Answer 75

Large Cell Carcinoma.

This is an undifferentiated malignant epithelial tumor that lacks the
cytologic features of small-cell carcinoma andglandular or squamous differentiation

. The cells
typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm (see Fig.
15-43D ).

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

Question 76

What is one histologic variant of Large Cell Carcinoma?

Answer 76

One histologic variant is large cell neuroendocrine carcinoma

Question 77

One histologic variant of large cell carcinoma is large cell neuroendocrine carcinoma.

This is recognized by
such features as :

Answer 77

• 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

Question 78

What is Combined Carcinoma?

Answer 78

Combined Carcinoma.

Approximately 10% of all lung carcinomas have a combined histology,
including two or more of the above types.

Question 79

Secondary Pathology.

What is the Secondary pathology of lung carcinomas?

Answer 79

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 and edema of the head and arm, 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.

Question 80

Answer 80

FIGURE 15-40 Precursor lesions of squamous cell carcinomas. Some of the earliest (and
“mild”) changes in smoking-damaged respiratory epithelium include goblet cell hyperplasia

(A), basal cell (or reserve cell) hyperplasia

(B), and squamous metaplasia

(C). More ominous changes include the appearance of squamous dysplasia

D), characterized by the presence of disordered squamous epithelium, with loss of nuclear polarity, nuclear hyperchromasia, pleomorphism, and mitotic figures. Squamous dysplasia may, in turn,
progress through the stages of mild, moderate, and severe dysplasia. Carcinoma-in-situ
(CIS)

(E) is the stage that immediately precedes invasive squamous carcinoma

(F), and apart from the lack of basement membrane disruption in CIS, the cytologic features are
similar to those in frank carcinoma. Unless treated, CIS will eventually progress to invasive
cancer.

Question 81

Answer 81

FIGURE 15-41 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.

Question 82

Answer 82

FIGURE 15-42 Cytologic diagnosis of lung cancer.

A sputum specimen shows an orangestaining,
keratinized squamous carcinoma cell with a prominent hyperchromatic nucleus
(arrow).

Note the size of the tumor cells compared with normal polymorphonuclear
leukocytes in the left lower corner .

Question 83

Answer 83

FIGURE 15-43 Histologic variants of lung carcinoma.

A, Gland-forming adenocarcinoma,
inset shows thyroid transcription factor 1 (TTF-1) positivity.

B, Well-differentiated
squamous cell carcinoma showing keratinization.

C, Small cell carcinoma with islands of
small deeply basophilic cells and areas of necrosis.

D, Large cell carcinoma, featuring
pleomorphic, anaplastic tumor cells with no squamous or glandular differentiation

Question 84

Answer 84

FIGURE 15-44 Bronchioloalveolar carcinoma, mucinous subtype, with characteristic
growth along pre-existing alveolar septa, without invasion.

Question 85

Answer 85

FIGURE 15-45 Atypical adenomatous hyperplasia with cuboidal epithelium and mild
interstitial fibrosis.

Question 86

Staging.
A uniform TNM system for staging cancer according to its anatomic extent at the time of
diagnosis is extremely useful, chiefly for comparing treatment results from different centers (
Table 15-11 ).

TABLE 15-11 – International Staging System for Lung Cancer

T1

Answer 86

Tumor <3 cm without pleural or main stem bronchus involvement (T1a, <2
cm; T1b, 2–3 cm)

Question 87

What T2

Answer 87

T2 Tumor 3–7 cm or involvement of main stem bronchus 2 cm from carina, visceral pleural involvement, or lobar atelectasis (T2a, 3–5 cm; T2b, 5–7
cm)

Question 88

T3

Answer 88

Tumor >7 cm or one with involvement of chest wall (including superior
sulcus tumors), diaphragm, mediastinal pleura, pericardium, main stem
bronchus 2 cm from carina, or entire lung atelectasis, or separate tumor
nodule(s) in the same lobe

Question 89

What is T4?

Answer 89

Tumor with invasion of mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina or separate tumor nodules in a
different ipsilateral lobe

Question 90

TABLE 15-11 – International Staging System for Lung Cancer

N0

Answer 90

N0 No demonstrable metastasis to regional lymph nodes

Question 91

TABLE 15-11 – International Staging System for Lung Cancer

N1

Answer 91

Ipsilateral hilar or peribronchial nodal involvement

Question 92

TABLE 15-11 – International Staging System for Lung Cancer

N2

Answer 92

Metastasis to ipsilateral mediastinal or subcarinal lymph nodes

Question 93

TABLE 15-11 – International Staging System for Lung Cancer

M0

Answer 93

No distant metastasis

Question 94

M1

Answer 94

Distant metastasis (M1a, separate tumor nodule in contralateral lobe or
pleural nodules or malignant pleural effusion; M1b, distant metastasis)

Question 95

Stage Ia

Answer 95

• T1
• N0
• M0

Question 96

Stage Ib

Answer 96

• T2
• N0
• M0

Question 97

Stage IIa

Answer 97

• T1
• N1
• M0

Question 98

Stage IIb

Answer 98

T2 N1 M0

T3 N0 M0

Question 99

Stage IIIa

Answer 99

T1–3 N2 M0
T3 N1 M0

Question 100

Stage IIIb

Answer 100

Any T N3 M0
T3 N2 M0
T4 Any N M0

Question 101

Stage IV

Answer 101

Any T Any N M1

Question 102

Lung cancer is one of the most insidious and aggressive neoplasms in the realm of oncology.

In the usual case it is discovered in patients in their 50s 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; unless resected, they kill by suffocation.

Question 103

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Pneumonia, abscess, lobar
collapse

Answer 103

Tumor obstruction of airway

Question 104

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Lipoid pneumonia

Answer 104

Tumor obstruction; accumulation of cellular lipid in foamy
macrophages

Question 105

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Pleural effusion

Answer 105

Tumor spread into pleura

Question 106

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Hoarseness

Answer 106

Recurrent laryngeal nerve invasion

Question 107

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Dysphagia

Answer 107

Esophageal invasion

Question 108

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Diaphragm paralysis

Answer 108

Phrenic nerve invasion

Question 109

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Rib destruction

Answer 109

Chest wall invasion

Question 110

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

SVC syndrome

Answer 110

SVC compression by tumor

Question 111

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Horner syndrome

Answer 111

Sympathetic ganglia invasion

Question 112

TABLE 15-12 – Local Effects of Lung Tumor Spread

Clinical Feature

Pericarditis, tamponade

Answer 112

Pericardial involvement

Question 113

The outlook is poor for most patients with lung carcinoma. Despite all efforts at early diagnosis
by frequent radiologic examination of the chest, cytologic examination of sputum, and bronchial
washings or brushings and the many improvements in thoracic surgery, radiation therapy, and
chemotherapy, the overall 5-year survival rate is only 15%.

Question 114

In many large clinics, not more than
20% to 30% of lung cancer patients have lesions sufficiently localized to even permit 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 are usually
advanced by the time they are discovered. The survival rate is 48% for cases detected when
the disease is still localized.

Question 115

Only 15% of lung cancers are diagnosed at this early stage, some of which can be cured by lobectomy or pneumonectomy.

Late-stage disease is usually treated
with palliative chemotherapy and/or radiation therapy.

Treatment of patients with
adenocarcinoma and activating mutations in EGFR with inhibitors of EGFR prolongs survival.

Many tumors that recur carry new mutations that generate resistance to these inhibitors,
proving that these drugs are “hitting” their target. In contrast, activating KRAS mutations appear
to be associated with a worse prognosis, regardless of treatment, in an already grim disease.
Untreated, the survival time for patients with small-cell carcinoma is 6 to 17 weeks. This cancer
is particularly sensitive to radiation therapy and chemotherapy, and potential cure rates of 15%
to 25% for limited disease have been reported in some centers

. Most patients have distant
metastases at diagnosis. Thus, even with treatment, the mean survival after diagnosis is only
about 1 year

Question 116

Paraneoplastic Syndromes

Lung carcinoma can be associated with several paraneoplastic syndromes [158] ( Chapter 7 ),
some of which may antedate the development of a detectablepulmonary lesion. The hormones
or hormone-like factors elaborated include:

Answer 116

• Antidiuretic hormone (ADH), inducing hyponatremia due 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

Question 117

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 carcinoid tumors,
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.

Question 118

Other systemic manifestations of lung carcinoma include the :

Answer 118

• 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 [158] ;
• 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

Question 119

What is Pancoast tumors?

Answer 119

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.

Question 120

NEUROENDOCRINE PROLIFERATIONS AND TUMORS

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 seems to be a precursor to the
development of multiple tumorlets and typical or atypical carcinoids

Question 121

Neoplasms of neuroendocrine cells in the lung include

Answer 121

• benign tumorlets,
• small,
• inconsequential,
• hyperplastic nests of 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.

Question 122

Neuroendocrine tumors 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 1.

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.

Question 123

What are carcinoid tumors?

Answer 123

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.

Question 124

Carcinoid tumors are low-grade malignant epithelial
neoplasms that are subclassified into :

Answer 124

typical and atypical carcinoids.

Question 125

What is typical carcinoid?

Answer 125

Typical carcinoids have no
p53 mutationsorabnormalities of BCL2 and BAX expression

Question 126

atypical carcinoids show :

.

Answer 126

p53 mutations or abnormalities of BCL2 and BAX expression
these changes in 20% to 40% and 10% to 20% of tumors, respectively.

Question 127

Some carcinoids also
show loss of heterozygosity at 3p, 13q14 (RB1), 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

Question 128

Carcinoids may arise centrally or may be peripheral. On gross examination, the
central tumors grow as :

Answer 128

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 collar-button lesion.

Peripheral tumors are
solid and nodular.

Spread to local lymph nodes at the time of resection is more likely with
atypical carcinoid.

Question 129

What is the histological appearance of carcinoid?

Answer 129

Histologically, the tumor is composed of organoid, trabecular, palisading, ribbon, or rosettelike
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 (see Fig. 15-46B ).

Typical
carcinoids have fewer than two mitoses per ten high-power fields and lack necrosis, while
atypical carcinoids have between two and ten mitoses per ten high-power fields and/or foci of
necrosis. [159]

Atypical carcinoids also show increased pleomorphism, have more prominent
nucleoli, and are more likely to grow in a disorganized fashion and invade lymphatics. On
electron microscopy the cells exhibit the dense-core granules characteristic of other
neuroendocrine tumors and, by immunohistochemistry, are found to contain serotonin,
neuron-specific enolase, bombesin, calcitonin, or other peptides.

Question 130

Answer 130

FIGURE 15-46 Bronchial carcinoid. A, Carcinoid growing as a spherical, pale mass
(arrow) protruding into the lumen of the bronchus. B, Histologic appearance,
demonstrating small, rounded, uniform nuclei and moderate cytoplasm.

Question 131

MISCELLANEOUS TUMORS

Lesions of the complex category of benign and malignant mesenchymal tumors, such as
:may occur but are rare.

Answer 131

• inflammatory myofibroblastic tumor,
• fibroma
• , fibrosarcoma,
• lymphangioleiomyomatosis,
• leiomyoma,
• leiomyosarcoma,
• lipoma,
• hemangioma,
• hemangiopericytoma,
• and chondroma,

Question 132

Benign and malignant hematopoietic 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.

Answer 132

These include:

• Langerhans cell histiocytosis,
• non-Hodgkin a
• nd Hodgkin lymphomas,
• lymphomatoid
• granulomatosis, an unusual EBV-positive B cell lymphoma,
• and lowgrade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue ( Chapter 13 ).

Question 133

What is a lung hamartoma?

Answer 133

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 these
tumors are peripheral, solitary, less than 3 to 4 cm in diameter, and well circumscribed.

Question 134

Pulmonary hamartoma consists of nodules of

Answer 134

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 ( Fig. 15-47 ).

The traditional term
hamartoma is retained for this lesion, but several features suggest that it is a neoplasm rather
than a malformation, such as its rarity in childhood, its increasing incidence with age, and the
finding of chromosomal aberrations involving either 6p21 or 12q14–q15, indicating a clonal
origin.

Question 135

Answer 135

FIGURE 15-47 Pulmonary hamartoma. There are islands of cartilage and entrapped
respiratory epithelium.

Question 136

What is inflammatory myofibroblastic tumor?

Answer 136

Inflammatory myofibroblastic tumor , though 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 spindleshaped
fibroblasts and myofibroblasts, lymphocytes, plasma cells, and peripheral fibrosis.

Question 137

What is the pathogenesis of inflammatory myofibroblastic tumor?

Answer 137

The
anaplastic lymphoma kinase (ALK) gene, located on 2p23, has been implicated in the
pathogenesis of this tumor.

Question 138

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.

Question 139

TABLE 15-13 – Mediastinal Tumors and Other Masses

SUPERIOR MEDIASTINUM

Answer 139

• Lymphoma
• Thymoma
• Thyroid lesions
• Metastatic
• carcinoma
• Parathyroid tumors

Question 140

TABLE 15-13 – Mediastinal Tumors and Other Masses

ANTERIOR MEDIASTINUM

Answer 140

• Thymoma
• Teratoma
• Lymphoma
• Thyroid lesions
• Parathyroid
• tumors

Question 141

TABLE 15-13 – Mediastinal Tumors and Other Masses

POSTERIOR MEDIASTINUM

Answer 141

• Neurogenic tumors (schwannoma,
• neurofibroma)
• Lymphoma
• Gastroenteric hernia

Question 142

TABLE 15-13 – Mediastinal Tumors and Other Masses

MIDDLE MEDIASTINUM

Answer 142

• Bronchogenic
• cyst
• Pericardial cyst
• Lymphoma

Question 143

What is the most common site of metastatic neoplasms?

Answer 143

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.

Question 144

Growth of contiguous tumors into the lungs occurs most often with:

Answer 144

esophageal
carcinomas and mediastinal lymphomas

Question 145

What is the morphology of metastatic growth within the lungs?

Answer 145

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, more
being at the periphery ( Fig. 15-48 ).

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.

Question 146

Answer 146

FIGURE 15-48 Numerous metastases to lung from a renal cell carcinoma