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.
Nonmucinous bronchioloalveolar carcinomas often ____________
consist of a peripheral lung nodule with
only rare aerogenous spread and therefore are amenable to surgical resection with an
excellent 5-year survival.
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 and thus 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 thentransforms into invasive adenocarcinoma.
This is supported by :
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]
Microscopically, atypical adenomatous hyperplasia is recognized as a :
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
What is Squamous Cell Carcinoma?
. Squamous cell carcinoma is most commonly found in men and
is closely correlated with a smoking history.
What is the characteristic of Squamous cells carcinoma histologically?
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 ).
What type of lung carcinoma shows the highest frequency of p53 mutatations?
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
What is small cell carcinoma?
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”
What is Azzopardi effect?
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
All small cell carcinomas are high grade.
T or F
True
A single variant of small cell
carcinoma is recognized:
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.
What is the electron microscopic appearanc of small cell carcinoma?
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.
This lung cancer type is most commonly associated with ectopic hormone production (discussed later).
Small cell carcinoma
Small cell carcinomas have a strong relationship to cigarette smoking
T or F
True
; only about 1% occur in
nonsmokers.
They may arise in major bronchi or in the periphery of the lung.
Small cell carcinoma has a preinvasive phase or carcinoma in situ.
T or F
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! ; )
What is most commonly mutated in Small cell carcinoma?
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.
What is Large Cell Carcinoma?
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
What is one histologic variant of Large Cell Carcinoma?
One histologic variant is large cell neuroendocrine carcinoma
One histologic variant of large cell carcinoma 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
What is Combined Carcinoma?
Combined Carcinoma.
Approximately 10% of all lung carcinomas have a combined histology,
including two or more of the above types.
Secondary Pathology.
What is the Secondary pathology of lung carcinomas?
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.
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.
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
Tumor <3 cm without pleural or main stem bronchus involvement (T1a, <2
cm; T1b, 2–3 cm)
What T2
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)
T3
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
What is T4?
Tumor with invasion of mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina or separate tumor nodules in a
different ipsilateral lobe
TABLE 15-11 – International Staging System for Lung Cancer
N0
N0 No demonstrable metastasis to regional lymph nodes
TABLE 15-11 – International Staging System for Lung Cancer
N1
Ipsilateral hilar or peribronchial nodal involvement
TABLE 15-11 – International Staging System for Lung Cancer
N2
Metastasis to ipsilateral mediastinal or subcarinal lymph nodes
TABLE 15-11 – International Staging System for Lung Cancer
M0
No distant metastasis
M1
Distant metastasis (M1a, separate tumor nodule in contralateral lobe or pleural nodules or malignant pleural effusion; M1b, distant metastasis)
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
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.
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Pneumonia, abscess, lobar
collapse
Tumor obstruction of airway
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Lipoid pneumonia
Tumor obstruction; accumulation of cellular lipid in foamy
macrophages
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Pleural effusion
Tumor spread into pleura
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Hoarseness
Recurrent laryngeal nerve invasion
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Dysphagia
Esophageal invasion
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Diaphragm paralysis
Phrenic nerve invasion
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Rib destruction
Chest wall invasion
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
SVC syndrome
SVC compression by tumor
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Horner syndrome
Sympathetic ganglia invasion
TABLE 15-12 – Local Effects of Lung Tumor Spread
Clinical Feature
Pericarditis, tamponade
Pericardial involvement
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%.
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.
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
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:
- 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
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.
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 [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
What is Pancoast tumors?
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
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
Neoplasms of neuroendocrine cells in the lung include
- 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.
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.
What are 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.
Carcinoid tumors are low-grade malignant epithelial
neoplasms that are subclassified into :
typical and atypical carcinoids.
What is typical carcinoid?
Typical carcinoids have no
p53 mutationsorabnormalities of BCL2 and BAX expression
atypical carcinoids show :
.
p53 mutations or abnormalities of BCL2 and BAX expression
these changes in 20% to 40% and 10% to 20% of tumors, respectively.
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
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 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.
What is the histological appearance of carcinoid?
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.
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.
MISCELLANEOUS TUMORS
Lesions of the complex category of benign and malignant mesenchymal tumors, such as
:may occur but are rare.
- inflammatory myofibroblastic tumor,
- fibroma
- , fibrosarcoma,
- lymphangioleiomyomatosis,
- leiomyoma,
- leiomyosarcoma,
- lipoma,
- hemangioma,
- hemangiopericytoma,
- and chondroma,
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.
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 ).
What is a lung hamartoma?
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.
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 ( 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.
FIGURE 15-47 Pulmonary hamartoma. There are islands of cartilage and entrapped
respiratory epithelium.
What is inflammatory myofibroblastic tumor?
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.
What is the pathogenesis of inflammatory myofibroblastic tumor?
The
anaplastic lymphoma kinase (ALK) gene, located on 2p23, has been implicated in the
pathogenesis of this tumor.
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
TABLE 15-13 – Mediastinal Tumors and Other Masses
ANTERIOR MEDIASTINUM
- Thymoma
- Teratoma
- Lymphoma
- Thyroid lesions
- Parathyroid
- tumors
TABLE 15-13 – Mediastinal Tumors and Other Masses
POSTERIOR MEDIASTINUM
- Neurogenic tumors (schwannoma,
- neurofibroma)
- Lymphoma
- Gastroenteric hernia
TABLE 15-13 – Mediastinal Tumors and Other Masses
MIDDLE MEDIASTINUM
- Bronchogenic
- cyst
- Pericardial cyst
- Lymphoma
What is the most common site of metastatic neoplasms?
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
What is the morphology of metastatic growth within the lungs?
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.
FIGURE 15-48 Numerous metastases to lung from a renal cell carcinoma
