NEOPLASMS

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LUNG CANCER
SMALL CELL CANCER
1. General Information About Small Cell Lung
Cancer (SCLC) SCLC accounts for approximately 15% of
bronchogenic carcinomas.
At the time of diagnosis, approximately 30% of patients with
SCLC will have tumors confined to the hemithorax of origin,
the mediastinum, or the supraclavicular lymph nodes. These
patients are designated as having limited-stage disease (LD).
[1] Patients with tumors that have spread beyond the
supraclavicular areas are said to have extensive-stage
disease (ED).
SCLC is more responsive to chemotherapy and radiation
therapy than other cell types of lung cancer; however, a cure
is difficult to achieve because SCLC has a greater tendency
to be widely disseminated by the time of diagnosis.show
more

2. Cellular Classification of SCLC

Pathologic

Classification
Before initiating treatment of a patient with small cell lung
cancer (SCLC), an experienced lung cancer pathologist
should review the pathologic material.
Pathologic Classification

The current classification of subtypes of SCLC includes the

following:[1]
Small cell carcinoma.
Combined small cell carcinoma (i.e., SCLC combined with
neoplastic squamous and/or glandular components).

SCLC arising from neuroendocrine cells forms one extreme of

the spectrum of neuroendocrine carcinomas of the lung.
Neuroendocrine tumors include the following: show more

3. Stage Information for SCLC Stage Information for

SCLC

Staging Systems

Limited-Stage Disease

Extensive-Stage Disease

IASLC-AJCC TNM Staging System

Staging Evaluation
Staging Systems

Several staging systems have been proposed for small cell

lung cancer (SCLC). These staging systems include the
following:
American Joint Committee on Cancer (AJCC) Tumor, Node,
and Metastasis (TNM).[1]

Veterans Administration Lung Study Group (VALG).[2]

International Association for the Study of Lung Cancer

(IASLC).[3] show more

4. Treatment Option Overview for SCLCTreatment

Option Overview for SCLC

Chemotherapy

Radiation Therapy
Chemotherapy and radiation therapy have been shown to improve
survival for patients with small cell lung cancer (SCLC).
Chemotherapy
Chemotherapy improves the survival of patients with show more

5. Limited-Stage SCLC Treatment show more

Chemotherapy and radiation therapy

Combined-modality treatment with etoposide and cisplatin with

thoracic radiation therapy (TRT) is the most widely used treatment for
patients with limited-stage disease (LD) SCLC.
Evidence (combined modality treatment):
1.
Survival. The following results have been reported in clinical trials:
a.

Mature results of prospective randomized trials suggest that

combined-modality therapy produces a modest but significant improvement
in survival of 5% at 3 years compared with chemotherapy alone.[1-3][Level
of evidence: 1iiA]

b.

Clinical trials have consistently achieved median survivals of 18

to 24 months and 40% to 50% 2-year survival rates with less than a 3%
treatment-related mortality.[3-7][Level of evidence: 1iiA]

c.
16]

No consistent survival benefit has resulted from the following:[8-

Increased dose intensity.

Increased dose density.show more

General Information About Small Cell Lung Cancer

(SCLC)
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General Information About Small Cell Lung Cancer (SCLC)

Incidence and Mortality

Clinical Features

Diagnosis

Prognosis and Survival

SCLC accounts for approximately 15% of bronchogenic
carcinomas.
At the time of diagnosis, approximately 30% of patients with SCLC
will have tumors confined to the hemithorax of origin, the
mediastinum, or the supraclavicular lymph nodes. These patients
are designated as having limited-stage disease (LD).[1] Patients
with tumors that have spread beyond the supraclavicular areas
are said to have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy

than other cell types of lung cancer; however, a cure is difficult to
achieve because SCLC has a greater tendency to be widely
disseminated by the time of diagnosis.
Incidence and Mortality

The overall incidence and mortality rates of SCLC in the United

States have decreased during the past few decades.[2]
Estimated new cases and deaths from lung cancer (SCLC and nonsmall cell lung cancer [NSCLC] combined) in the United States in
2015:[3]
New cases: 221,200.

Deaths: 158,040.
Clinical Features

Lung cancer may present with symptoms or be found incidentally

on chest imaging. Symptoms and signs may result from the
location of the primary local invasion or compression of adjacent
thoracic structures, distant metastases, or paraneoplastic
phenomena. The most common symptoms at presentation are
worsening cough, shortness of breath, and dyspnea. Other
presenting symptoms include the following:
Chest pain.

Hoarseness.

Malaise.

Anorexia.

Weight loss.

Hemoptysis.
Symptoms may result from local invasion or compression of
adjacent thoracic structures, such as compression involving the
esophagus causing dysphagia, compression involving the
laryngeal nerves causing hoarseness, or compression involving
the superior vena cava causing facial edema and distension of the
superficial veins of the head and neck. Symptoms from distant
metastases may also be present and include neurological defect
or personality change from brain metastases or pain from bone
metastases.

Infrequently, patients with SCLC may present with symptoms and

signs of one of the following paraneoplastic syndromes:
Inappropriate antidiuretic hormone secretion.

Cushing syndrome from secretion of adrenocorticotropic

hormone.

Paraneoplastic cerebellar degeneration.

Lambert-Eaton myasthenic syndrome.[2]

Physical examination may identify enlarged supraclavicular
lymphadenopathy, pleural effusion or lobar collapse, unresolved
pneumonia, or signs of associated disease such as chronic
obstructive pulmonary disease.
Diagnosis

Treatment options for patients are determined by histology, stage,

and general health and comorbidities of the patient.
Investigations of patients with suspected SCLC focus on
confirming the diagnosis and determining the extent of the
disease.
The procedures used to determine the presence of cancer include
the following:
History.

Physical examination.

Routine laboratory evaluations.

Chest x-ray.

Chest computed tomography scan with infusion of contrast

material.

Biopsy.
Before a patient begins lung cancer treatment, an experienced
lung cancer pathologist must review the pathologic material. This
is critical because SCLC, which responds well to chemotherapy
and is generally not treated surgically, can be confused on
microscopic examination with NSCLC.[4] Immunohistochemistry
and electron microscopy are invaluable techniques for diagnosis
and subclassification, but most lung tumors can be classified by
light microscopic criteria.

(Refer to the Staging Evaluation section in the Stage Information

for SCLC section of this summary for more information about tests
and procedures used for staging.)
Prognosis and Survival
Regardless of stage, the current prognosis for patients with SCLC
is unsatisfactory despite improvements in diagnosis and therapy
made during the past 25 years. Without treatment, SCLC has the
most aggressive clinical course of any type of pulmonary tumor,
with median survival from diagnosis of only 2 to 4 months. About
10% of the total population of SCLC patients remains free of
disease during the 2 years from the start of therapy, which is the
time period during which most relapses occur. Even these
patients, however, are at risk of dying from lung cancer (both
small and non-small cell types).[5] The overall survival at 5 years
is 5% to 10%.[1,5-7]
An important prognostic factor for SCLC is the extent of disease.
Patients with LD have a better prognosis than patients with ED.
For patients with LD, median survival of 16 to 24 months and 5year survivals of 14% with current forms of treatment have been
reported.[1,6,8,9] Patients diagnosed with LD who smoke should
be encouraged to stop smoking before undergoing combinedmodality therapy because continued smoking may compromise
survival.[10]
Improved long-term survival in patients with LD has been shown
with combined-modality therapy.[9,11][Level of evidence: 1iiA]
Although long-term survivors have been reported among patients
who received either surgery or chemotherapy alone,
chemotherapy combined with thoracic radiation therapy (TRT) is
considered the standard of care.[12] Adding TRT increases
absolute survival by approximately 5% over chemotherapy alone.
[11,13] The optimal timing of TRT relative to chemotherapy has
been evaluated in multiple trials and meta-analyses with the
weight of evidence suggesting a small benefit to early TRT.
[1,14,15][Level of evidence: 1iiA]
In patients with ED, median survival of 6 to 12 months is reported
with currently available therapy, but long-term disease-free
survival is rare.
Prophylactic cranial radiation prevents central nervous system
recurrence and can improve survival in patients who have had a

complete response to chemoradiation.[16,17][Level of evidence:

1iiA]
Thoracic radiation may also improve long-term outcomes for
these patients.[18]
All patients with this type of cancer may appropriately be
considered for inclusion in clinical trials at the time of diagnosis.
Information about ongoing clinical trials is available from the NCI
Web site.

Cellular Classification of SCLC

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Cellular Classification of SCLC

Pathologic Classification
Before initiating treatment of a patient with small cell lung cancer
(SCLC), an experienced lung cancer pathologist should review the
pathologic material.
Pathologic Classification

The current classification of subtypes of SCLC includes the

following:[1]
Small cell carcinoma.
Combined small cell carcinoma (i.e., SCLC combined with
neoplastic squamous and/or glandular components).

SCLC arising from neuroendocrine cells forms one extreme of the

spectrum of neuroendocrine carcinomas of the lung.
Neuroendocrine tumors include the following:
Low-grade typical carcinoid.

Intermediate-grade atypical carcinoid.

High-grade neuroendocrine tumors including large-cell

neuroendocrine carcinoma (LCNEC) and SCLC.
Because of differences in clinical behavior, therapy, and
epidemiology, these tumors are classified separately in the World
Health Organization (WHO) revised classification. The variant form
of SCLC called mixed small cell/large cell carcinoma was not
retained in the revised WHO classification. Instead, SCLC is now

described with only one variant, SCLC combined, when at least

10% of the tumor bulk is made of an associated non-small cell
component.
SCLC presents as a proliferation of small cells with the following
morphological features:[2]
Scant cytoplasm.

Ill-defined borders.

Finely granular "salt and pepper" chromatin.

Absent or inconspicuous nucleoli.

Frequent nuclear molding.

A high mitotic count.

Combined small cell carcinoma includes a mixture of small cell
and large cell or any other non-small cell component. Any cases
showing at least 10% of SCLC are diagnosed as combined SCLC,
and SCLC is limited to tumors with pure SCLC histology. SCLC
associated with LCNEC is diagnosed as SCLC combined with
LCNEC.
Nearly all SCLC are immunoreactive for keratin, thyroid
transcription factor 1, and epithelial membrane antigen.
Neuroendocrine and neural differentiation result in the expression
of dopa decarboxylase, calcitonin, neuron-specific enolase,
chromogranin A, CD56 (also known as nucleosomal histone kinase
1 or neural-cell adhesion molecule), gastrin-releasing peptide, and
insulin-like growth factor 1. One or more markers of
neuroendocrine differentiation can be found in approximately 75%
of SCLC.[3]
Although preinvasive and in situ malignant changes are
frequently found in patients with non-small cell lung cancer, these
findings are rare in patients with SCLC.[4]

General Information About Non-Small Cell Lung

Cancer (NSCLC)
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General Information About Non-Small Cell Lung Cancer

(NSCLC)

Incidence and Mortality

Anatomy

Pathogenesis

Pathology

Risk Factors

Prevention

Screening

Clinical Features

Diagnosis

Molecular Features

Prognostic Factors

Related Summaries
NSCLC is any type of epithelial lung cancer other than small cell
lung cancer (SCLC). The most common types of NSCLC are
squamous cell carcinoma, large cell carcinoma, and

adenocarcinoma, but there are several other types that occur less
frequently, and all types can occur in unusual histologic variants.
Although NSCLCs are associated with cigarette smoke,
adenocarcinomas may be found in patients who have never
smoked. As a class, NSCLCs are relatively insensitive to
chemotherapy and radiation therapy compared with SCLC.
Patients with resectable disease may be cured by surgery or
surgery followed by chemotherapy. Local control can be achieved
with radiation therapy in a large number of patients with
unresectable disease, but cure is seen only in a small number of
patients. Patients with locally advanced unresectable disease may
achieve long-term survival with radiation therapy combined with
chemotherapy. Patients with advanced metastatic disease may
achieve improved survival and palliation of symptoms with
chemotherapy, targeted agents, and other supportive measures.
Incidence and Mortality

Estimated new cases and deaths from lung cancer (NSCLC and
SCLC combined) in the United States in 2014:[1]
New cases: 224,210.

Deaths: 159,260.
Lung cancer is the leading cause of cancer-related mortality in the
United States.[1] The 5-year relative survival rate from 1995 to
2001 for patients with lung cancer was 15.7%. The 5-year relative
survival rate varies markedly depending on the stage at
diagnosis, from 49% to 16% to 2% for patients with local,
regional, and distant stage disease, respectively.[2]
Anatomy
NSCLC arises from the epithelial cells of the lung of the central
bronchi to terminal alveoli. The histological type of NSCLC
correlates with site of origin, reflecting the variation in respiratory
tract epithelium of the bronchi to alveoli. Squamous cell
carcinoma usually starts near a central bronchus.
Adenocarcinoma and bronchioloalveolar carcinoma usually
originate in peripheral lung tissue.
Enlarge
Anatomy of the respiratory system.
Pathogenesis

Smoking-related lung carcinogenesis is a multistep process.

Squamous cell carcinoma and adenocarcinoma have defined
premalignant precursor lesions. Before becoming invasive, lung
epithelium may undergo morphological changes that include the
following:
Hyperplasia.

Metaplasia.

Dysplasia.

Carcinoma in situ.
Dysplasia and carcinoma in situ are considered the principal
premalignant lesions because they are more likely to progress to
invasive cancer and less likely to spontaneously regress.
In addition, after resection of a lung cancer, there is a 1% to 2%
risk per patient per year that a second lung cancer will occur.[3]
Pathology

NSCLC is a heterogeneous aggregate of histologies. The most

common histologies include the following:
Epidermoid or squamous cell carcinoma.

Adenocarcinoma.

Large cell carcinoma.

These histologies are often classified together because
approaches to diagnosis, staging, prognosis, and treatment are
similar.
Risk Factors

Several risk factors contribute to the development of lung cancer.

These risk factors may include the following:
Cigarette, pipe, or cigar smoking.

Exposure to second-hand smoke, radon, arsenic, asbestos,

chromates, chloromethyl ethers, nickel, polycyclic aromatic
hydrocarbons, radon progeny, other agents, and air pollution.[4]

Radiation therapy to the breast or chest.

The single most important risk factor for the development of lung
cancer is smoking. For smokers, the risk for lung cancer is on
average tenfold higher than in lifetime nonsmokers (defined as a

person who has smoked <100 cigarettes in his or her lifetime).

The risk increases with the quantity of cigarettes, duration of
smoking, and starting age.
Smoking cessation results in a decrease in precancerous lesions
and a reduction in the risk of developing lung cancer. Former
smokers continue to have an elevated risk for lung cancer for
years after quitting. Asbestos exposure may exert a synergistic
effect of cigarette smoking on the lung cancer risk.[4]
Prevention
A significant number of patients cured of their smoking-related
lung cancer may develop a second malignancy. In the Lung
Cancer Study Group trial of 907 patients with stage T1, N0
resected tumors, the rate was 1.8% per year for nonpulmonary
second cancers and 1.6% per year for new lung cancers.[5] Other
studies have reported even higher risks of second tumors in longterm survivors, including rates of 10% for second lung cancers
and 20% for all second cancers.[6]
Because of the persistent risk of developing second lung cancers
in former smokers, various chemoprevention strategies have been
evaluated in randomized control trials. None of the phase III trials
with the agents beta carotene, retinol, 13-cis-retinoic acid,
[alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has
demonstrated beneficial, reproducible results.[7-11][Level of
evidence: 1iiA] Chemoprevention of second primary cancers of
the upper aerodigestive tract is undergoing clinical evaluation in
patients with early-stage lung cancer.
Refer to the PDQ summaries on Lung Cancer
Prevention and Smoking in Cancer Care for more information.
Screening
In patients considered at high risk for developing lung cancer, the
only screening modality for early detection that has been shown
to alter mortality is low-dose helical CT scanning.[12] Studies of
lung cancer screening with chest radiography and sputum
cytology have failed to demonstrate that screening lowers lung
cancer mortality rates.
(Refer to the Screening by low-dose helical computed
tomography subsection in the PDQ summary onLung Cancer
Screening for more information.)

Clinical Features

Lung cancer may present with symptoms or be found incidentally

on chest imaging. Symptoms and signs may result from the
location of the primary local invasion or compression of adjacent
thoracic structures, distant metastases, or paraneoplastic
phenomena. The most common symptoms at presentation are
worsening cough or chest pain. Other presenting symptoms
include the following:
Hemoptysis.

Malaise.

Weight loss.

Dyspnea.

Hoarseness.
Symptoms may result from local invasion or compression of
adjacent thoracic structures such as compression involving the
esophagus causing dysphagia, compression involving the
laryngeal nerves causing hoarseness, or compression involving
the superior vena cava causing facial edema and distension of the
superficial veins of the head and neck. Symptoms from distant
metastases may also be present and include neurological defect
or personality change from brain metastases or pain from bone
metastases. Infrequently, patients may present with symptoms
and signs of paraneoplastic diseases such as hypertrophic
osteoarthropathy with digital clubbing or hypercalcemia from
parathyroid hormone-related protein. Physical examination may
identify enlarged supraclavicular lymphadenopathy, pleural
effusion or lobar collapse, unresolved pneumonia, or signs of
associated disease such as chronic obstructive pulmonary disease
or pulmonary fibrosis.
Diagnosis
Treatment options for patients are determined by histology, stage,
and general health and comorbidities of the patient.
Investigations of patients with suspected NSCLC focus on
confirming the diagnosis and determining the extent of the
disease.

The procedures used to determine the presence of cancer include

the following:
History.

Physical examination.

Routine laboratory evaluations.

Chest x-ray.

Chest CT scan with infusion of contrast material.

Biopsy.
Before a patient begins lung cancer treatment, an experienced
lung cancer pathologist must review the pathologic material. This
is critical because SCLC, which responds well to chemotherapy
and is generally not treated surgically, can be confused on
microscopic examination with NSCLC.[13] Immunohistochemistry
and electron microscopy are invaluable techniques for diagnosis
and subclassification, but most lung tumors can be classified by
light microscopic criteria.
(Refer to the Staging Evaluation section of this summary for more
information on tests and procedures used for staging.)
Molecular Features
The identification of mutations in lung cancer has led to the
development of molecularly targeted therapy to improve the
survival of subsets of patients with metastatic disease.[14] In
particular, subsets of adenocarcinoma now can be defined by
specific mutations in genes encoding components of the
epidermal growth factor receptor (EGFR) and downstream
mitogen-activated protein kinases (MAPK) and
phosphatidylinositol 3-kinases (PI3K) signaling pathways. These
mutations may define mechanisms of drug sensitivity and primary
or acquired resistance to kinase inhibitors.
Other genetic abnormalities of potential relevance to treatment
decisions include translocations involving the anaplastic
lymphoma kinase (ALK)-tyrosine kinase receptor, which are
sensitive to ALK inhibitors, and amplification
of MET (mesenchymal epithelial transition factor), which encodes
the hepatocyte growth factor receptor. MET amplification has

been associated with secondary resistance to EGFR tyrosine

kinase inhibitors.
Prognostic Factors

Multiple studies have attempted to identify the prognostic

importance of a variety of clinicopathologic factors.[6,15-18]
Factors that have correlated with adverse prognosis include the
following:
Presence of pulmonary symptoms.

Large tumor size (>3 cm).

Nonsquamous histology.

Metastases to multiple lymph nodes within a TNM-defined nodal

station.[19-29] (Refer to theEvaluation of Mediastinal Lymph Node
Metastasis section of this summary for more information.)

Vascular invasion.[16,30-32]
For patients with inoperable disease, prognosis is adversely
affected by poor performance status and weight loss of more than
10%. These patients have been excluded from clinical trials
evaluating aggressive multimodality interventions.
In multiple retrospective analyses of clinical trial data, advanced
age alone has not been shown to influence response or survival
with therapy.[33]
Refer to the separate treatment sections for each stage of NSCLC
in this summary for more information about prognosis.
Because treatment is not satisfactory for almost all patients with
NSCLC, eligible patients should be considered for clinical trials.
Information about ongoing clinical trials is available from the NCI
Web site.
Related Summaries

Other PDQ summaries containing information related to lung

cancer include the following:
Lung Cancer Prevention

Lung Cancer Screening

Small Cell Lung Cancer Treatment

Smoking in Cancer Care

Cellular Classification of NSCLC

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Cellular Classification of NSCLC

WHO/IASLC Histologic Classification of NSCLC

Squamous cell carcinoma

Adenocarcinoma

Large cell carcinoma

Neuroendocrine tumors

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous

elements

Molecular Features
Malignant non-small cell epithelial tumors of the lung are
classified by the World Health Organization (WHO)/International
Association for the Study of Lung Cancer (IASLC). There are three
main subtypes of non-small cell lung cancer (NSCLC), including
the following:

Squamous cell carcinoma (25% of lung cancers).

Adenocarcinoma (40% of lung cancers).

Large cell carcinoma (10% of lung cancers).

There are numerous additional subtypes of decreasing frequency.
[1]
WHO/IASLC Histologic Classification of NSCLC

1. Squamous cell carcinoma.

a. Papillary.
b. Clear cell.
c. Small cell.
d. Basaloid.
2. Adenocarcinoma.
a. Acinar.
b. Papillary.
c. Bronchioloalveolar carcinoma.
i.
ii.
iii.
type.

Nonmucinous.
Mucinous.
Mixed mucinous and nonmucinous or indeterminate cell

d. Solid adenocarcinoma with mucin.

e. Adenocarcinoma with mixed subtypes.
f.

Variants.
i.
ii.

Well-differentiated fetal adenocarcinoma.

Mucinous (colloid) adenocarcinoma.

iii.

Mucinous cystadenocarcinoma.

iv.

Signet ring adenocarcinoma.

v.

Clear cell adenocarcinoma.

3. Large cell carcinoma.

a. Variants.

i.
ii.

Large cell neuroendocrine carcinoma (LCNEC).

Combined LCNEC.

iii.

Basaloid carcinoma.

iv.

Lymphoepithelioma-like carcinoma.

v.
vi.

Clear cell carcinoma.

Large cell carcinoma with rhabdoid phenotype.

4. Adenosquamous carcinoma.
5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous
elements.
a. Carcinomas with spindle and/or giant cells.
b. Spindle cell carcinoma.
c. Giant cell carcinoma.
d. Carcinosarcoma.
e. Pulmonary blastoma.
6. Carcinoid tumor.
a. Typical carcinoid.
b. Atypical carcinoid.
7. Carcinomas of salivary gland type.
a. Mucoepidermoid carcinoma.
b. Adenoid cystic carcinoma.
c. Others.
8. Unclassified carcinoma.
Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally,

in the larger bronchi of the lung. Squamous cell carcinomas are
linked more strongly with smoking than other forms of NSCLC. The
incidence of squamous cell carcinoma of the lung has been
decreasing in recent years.
Adenocarcinoma
Adenocarcinoma is now the most common histologic subtype in
many countries, and subclassification of adenocarcinoma is
important. One of the biggest problems with lung
adenocarcinomas is the frequent histologic heterogeneity. In fact,
mixtures of adenocarcinoma histologic subtypes are more
common than tumors consisting purely of a single pattern of
acinar, papillary, bronchioloalveolar, and solid adenocarcinoma
with mucin formation.
Criteria for the diagnosis of bronchioloalveolar carcinoma have
varied widely in the past. The current WHO/IASLC definition is
much more restrictive than that previously used by many
pathologists because it is limited to only noninvasive tumors.
If stromal, vascular, or pleural invasion are identified in an
adenocarcinoma that has an extensive bronchioloalveolar
carcinoma component, the classification would be an
adenocarcinoma of mixed subtype with predominant
bronchioloalveolar pattern and a focal acinar, solid, or papillary
pattern, depending on which pattern is seen in the invasive
component. However, the future of bronchioloalveolar carcinoma
as a distinct clinical entity is unclear; a multidisciplinary expert
panel representing the IASLC, the American Thoracic Society, and
the European Respiratory Society proposed a major revision of the
classification of adenocarcinomas in 2011 that entails a
reclassification of what was called bronchioloalveolar carcinoma
into newly defined histologic subgroups.

The following variants of adenocarcinoma are recognized in the

WHO/IASLC classification:

Well-differentiated fetal adenocarcinoma.

Mucinous (colloid) adenocarcinoma.

Mucinous cystadenocarcinoma.

Signet ring adenocarcinoma.

Clear cell adenocarcinoma.

Large cell carcinoma
In addition to the general category of large cell carcinoma,
several uncommon variants are recognized in the WHO/IASLC
classification, including the following:

LCNEC.

Basaloid carcinoma.

Lymphoepithelioma-like carcinoma.

Clear cell carcinoma.

Large cell carcinoma with rhabdoid phenotype.

Basaloid carcinoma is also recognized as a variant of squamous
cell carcinoma, and rarely, adenocarcinomas may have a basaloid
pattern; however, in tumors without either of these features, they
are regarded as a variant of large cell carcinoma.
Neuroendocrine tumors
LCNEC is recognized as a histologically high-grade non-small cell
carcinoma. It has a very poor prognosis similar to that of small
cell lung cancer (SCLC). Atypical carcinoid is recognized as an

intermediate-grade neuroendocrine tumor with a prognosis that

falls between typical carcinoid and high-grade SCLC and LCNEC.
Neuroendocrine differentiation can be demonstrated by
immunohistochemistry or electron microscopy in 10% to 20% of
common NSCLCs that do not have any neuroendocrine
morphology. These tumors are not formally recognized within the
WHO/IASLC classification scheme because the clinical and
therapeutic significance of neuroendocrine differentiation in
NSCLC is not firmly established. These tumors are referred to
collectively as NSCLC with neuroendocrine differentiation.
Carcinomas with pleomorphic, sarcomatoid, or sarcomatous
elements
This is a group of rare tumors. Spindle cell carcinomas and giant
cell carcinomas comprise only 0.4% of all lung malignancies, and
carcinosarcomas comprise only 0.1% of all lung malignancies. In
addition, this group of tumors reflects a continuum in histologic
heterogeneity as well as epithelial and mesenchymal
differentiation. On the basis of clinical and molecular data,
biphasic pulmonary blastoma is regarded as part of the spectrum
of carcinomas with pleomorphic, sarcomatoid, or sarcomatous
elements.
Molecular Features
The identification of mutations in lung cancer has led to the
development of molecularly targeted therapy to improve the
survival of subsets of patients with metastatic disease.[2] In
particular, subsets of adenocarcinoma now can be defined by
specific mutations in genes encoding components of the
epidermal growth factor receptor (EGFR) and downstream
mitogen-activated protein kinases (MAPK) and
phosphatidylinositol 3-kinases (PI3K) signaling pathways. These
mutations may define mechanisms of drug sensitivity and primary

or acquired resistance to kinase inhibitors. Other mutations of

potential relevance to treatment decisions include:

Kirsten rat sarcoma viral oncogene (KRAS).

Anaplastic lymphoma kinase receptor (ALK).

Human epidermal growth factor receptor 2 (HER2).

V-raf murine sarcoma viral oncogene homolog B1 (BRAF).

PIK3 catalytic protein alpha (PI3KCA).

AKT1.

MAPK kinase 1 (MAP2K1 or MEK1).

MET, which encodes the hepatocyte growth factor receptor

(HGFR).
These mutations are mutually exclusive, except for those in
PIK3CA and EGFR mutations and ALKtranslocations.[3]
EGFR and ALK mutations predominate in adenocarcinomas that
develop in nonsmokers, and KRASand BRAF mutations are more
common in smokers or former smokers. EGFR mutations strongly
predict the improved response rate and progression-free survival
of EGFR inhibitors. In a set of 2,142 lung adenocarcinoma
specimens from patients treated at Memorial Sloan Kettering
Cancer Center, EGFR exon 19 deletions and L858R were found in
15% of tumors from former smokers (181 of 1,218; 95% CI, 13
17), 6% from current smokers (20 of 344; 95% CI, 49), and 52%
from never-smokers (302 of 580; 95% CI, 4856; P < .001 for
ever- vs. never-smokers).[4]
Fusions of ALK with EML4 genes form translocation products that
occur in ranges from 3% to 7% in unselected NSCLC and are
responsive to pharmacological inhibition of ALK by agents such as

crizotinib. Other mutations that occur in less than 5% of NSCLC

tumors include:

HER2, present in 2% of tumors.

PI3KCA, present in 2% of tumors.

AKT1, present in 1% of tumors.

BRAF mutations, present in 1% to 3% of tumors.

BRAF mutations are mutually exclusive
of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also
known as MEK) have been identified in 1% of
NSCLC. MET oncogene encodes hepatocyte growth factor
receptor. Amplification of this gene has been associated with
secondary resistance to EGFR tyrosine kinase inhibitors.
References