Chapter 15:Lung:Tumors Flashcards
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.
Etiology of lung cancer
- Tobacco Smoking.
- Industrial Hazards.
- Air Pollution
- Molecular Genetics
- Precursor Lesions.
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 tenfold greater risk of developing lung
cancer, andheavy smokers (more than 40 cigarettes per day for several years)have a60-fold
greater risk.
Women have a higher susceptibility to tobacco carcinogens than men do.
T or F
True
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.
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.
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.
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
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)
More than 1200 substances have been counted in
cigarette smoke, many of which are potential carcinogens.
They include promoters, such as__________.
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
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.
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.
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 _______________-
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 )
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, KRAS, EGFR, c-MET , and c-KIT .
The commonly deleted or inactivated tumor suppressor genes in lung cancer include :
p53, RB1, p16(INK4a), and
multiple loci on chromosome 3p
At this locale there are numerous candidate tumor suppressor genes in lung cancer, such as FHIT , RASSF1A, and others that remain to be identified
Of the various cancer associated genes:
are most commonly involved in small cell lung carcinoma
- C-KIT (40–70%),
- MYCN and MYCL (20–30%),
- p53 (90%)
- , 3p (100%),
- RB (90%), and
- BCL2 (75–90%)
By
comparison, _________ are the ones most
commonly affected in non-small cell lung carcinoma.
- EGFR (25%),
- KRAS (10–15%),
- p53 (50%),
- p16 INK4a (70%)
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.
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.
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
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:
- 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]
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] :
- 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%)
TABLE 15-10 – Histologic Classification of Malignant Epithelial Lung Tumors
- Squamous cell carcinoma
- Small-cell carcinoma
- Combined small-cell
carcinoma
- Combined small-cell
- Adenocarcinoma
- Acinar; papillary, bronchioloalveolar, solid, mixed subtypes
- Large-cell carcinoma
- Large-cell neuroendocrine
carcinoma
- Large-cell neuroendocrine
- Adenosquamous carcinoma
- Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
- Carcinoid tumor
- Typical, atypical
- Carcinomas of salivary gland type
- Unclassified carcinoma
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]
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
There may be mixtures of histologic patterns, even in the same cancer.
T or F
True
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 (almost always 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.
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.
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?
adenocarcinomas, including those of the bronchioloalveolar type, to be discussed separately
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
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
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.
In almost all patterns the neoplastic tissue is gray-white and firm to hard.
T or F
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 (
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%.
What is Adenocarcinoma?
Adenocarcinoma.
This is a malignant epithelial tumor with glandular differentiation or mucin
production by the tumor cells.
Adenocarcinomas
grow in various patterns, including :
- acinar,
- papillary,
- bronchioloalveolar,
- and solid with mucin formation.
Of the types of pattern of adenocarcinoma, only pure
______________has distinct gross, microscopic, and clinical features and will be
discussed separately
bronchioloalveolar carcinoma
What type of lung cancer is the most common type of lung cancer in women and nonsmokers
Adenocarcinoma is the most common type of lung cancer in women and nonsmokers
As compared with squamous cell cancers, the lesions of adenocarcinoma are usually more _________
peripherally located, and
tend to be smaller.
Adenocarcinoma vary histologicall from what?
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.
In adenocarcinoma the majority are
positive for___________.
thyroid transcription factor-1 (TTF-1) and about 80% contain mucin
In adenocarcinoma 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.
T or F
True
What pattern of Adenocarcinoma has a better outcome than invasive carinomas of the same size?
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.
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).
What mutation occur primarily in adenocarcinoma?
**KRAS mutations** occur primarily in adenocarcinoma, and are seen at a much lower frequency in nonsmokers (5%) than in smokers (30%).
What mutations and inactivation in adenocarcinoma have the same frequency un sq cell carcinoma?
p53, RB1, and p16 mutations and inactivation
have the same frequency in adenocarcinoma as in squamous cell carcinoma.
What mutation and amplification in the __________ occur in patients with
adenocarcinoma (mostly women, nonsmokers, and those of Asian origin). [154]
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
What is bronchioalveolar carcinoma?
bronchioloalveolar carcinoma occurs in the pulmonary parenchyma in the terminal bronchioloalveolar regions.
It represents, in various series, 1% to 9% of all
lung cancers
.
In bronchioalveolar carcinoma 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, graywhite
areas that can be confused with pneumonia on gross inspection.
What is the histological appearance of the tumor of bronchioalveolar ca?
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.
What are the two subtypes of lepidic growth?
It has two subtypes: nonmucinous and mucinous.
What is the appearance of nonmucinous pattern?
The former has columnar, peg-shaped, or cuboidal cells.
What is the appearance of the mucinous growth?
while the latter has distinctive, tall,
columnar cells with cytoplasmic and intra-alveolar mucin, growing along the alveolar septa (
Fig. 15-44 ).
Ultrastructurally, bronchioloalveolar carcinomas are a heterogeneous group,
consisting of :
- 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.
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.
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.
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 .
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
FIGURE 15-44 Bronchioloalveolar carcinoma, mucinous subtype, with characteristic
growth along pre-existing alveolar septa, without invasion.
FIGURE 15-45 Atypical adenomatous hyperplasia with cuboidal epithelium and mild
interstitial fibrosis.
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.
FIGURE 15-47 Pulmonary hamartoma. There are islands of cartilage and entrapped
respiratory epithelium.
FIGURE 15-48 Numerous metastases to lung from a renal cell carcinoma
