Cellular Classification of NSCLC
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.
Nonmucinous.
ii.
Mucinous.
iii.
Mixed
mucinous and nonmucinous or indeterminate cell type.
d.
Solid
adenocarcinoma with mucin.
e.
Adenocarcinoma
with mixed subtypes.
f.
Variants.
i.
Well-differentiated
fetal adenocarcinoma.
ii.
Mucinous
(colloid) adenocarcinoma.
iii.
Mucinous
cystadenocarcinoma.
iv.
Signet
ring adenocarcinoma.
v.
Clear
cell adenocarcinoma.
3.
Large
cell carcinoma.
a.
Variants.
i.
Large
cell neuroendocrine carcinoma (LCNEC).
ii.
Combined
LCNEC.
iii.
Basaloid
carcinoma.
iv.
Lymphoepithelioma-like
carcinoma.
v.
Clear
cell carcinoma.
vi.
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, 4–9), and 52% from never-smokers (302 of
580; 95% CI, 48–56; 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
1.
Travis
WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural
tumours. 3rd ed. Berlin: Springer-Verlag, 1999.
2.
Pao
W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol
12 (2): 175-80, 2011. [PUBMED Abstract]
3.
Tiseo
M, Gelsomino F, Boggiani D, et al.: EGFR and EML4-ALK gene mutations in NSCLC:
a case report of erlotinib-resistant patient with both concomitant mutations.
Lung Cancer 71 (2): 241-3, 2011. [PUBMED Abstract]
4.
D'Angelo
SP, Pietanza MC, Johnson ML, et al.: Incidence of EGFR exon 19 deletions and
L858R in tumor specimens from men and cigarette smokers with lung
adenocarcinomas. J Clin Oncol 29 (15): 2066-70, 2011. [PUBMED Abstract]
