LARGE CELL LUNG CARCINOMA

Large cell lung carcinoma (LCLC) is an undifferentiated malignancy
without features of small cell carcinoma, squamous
cell carcinoma, or adenocarcinoma. 60 Although the cell of origin
of LCLC is not well defined, ultrastructural studies have
revealed features of glandular or squamous differentiation that
cannot be appreciated by light microscopy. LCLC thus represents
an extremely poorly differentiated NSCLC without
histological features that permit ready assignment to one of the
more usual and better-differentiated forms of lung carcinoma.
With loss of differentiating features comes extremely aggressive
biological behavior. These tumors comprise approximately 9%
of primary lung malignancies. 108
Histology of Large Cell Lung Carcinoma LCLCs are
composed of poorly differentiated large cells ( 21 microns)
with prominent nucleoli and abundant, clearly visible cytoplasm
(Fig. 22.7). Cells and nuclei are usually separate and
discrete and less prone to deformation than the cells of small
cell carcinoma. Tumor cells are generally arranged in nests or
sheets. Nuclei are large and N/C ratios may be high. Mitoses
are numerous and areas of necrosis are common.
The category of LCLC is heterogeneous and several variants
of this tumor type have been described based on histology and
immunohistochemical properties. These include clear cell carcinoma,
large cell carcinoma with rhabdoid phenotype (rhabdoid
carcinoma), and lymphoepithelioma-like carcinoma as well as
two variants discussed elsewhere in this chapter, basaloid carcinoma
and large cell neuroendocrine carcinoma (LCNEC).
Clear cell carcinoma and rhabdoid carcinoma are terms that
convey the essential cytological appearances of these neoplasms.
The rhabdoid type has a particularly poor prognosis. 109–112
The lymphoepithelioma-like variant resembles the lymphoepithelial
carcinoma seen in the nasopharynx (undifferentiated
epithelial cells with an intermixed prominent lymphoid infiltrate);
this rare variant that affects young, Asian, nonsmokers 113,114 is
associated with Epstein-Barr virus (EBV). These tumors are Bcl-2
positive by immunohistochemistry (IHC) and express EBER-1
by in situ hybridization, 114 suggesting viral etiology. Surgery is the
treatment for early stage tumors, while multimodality treatment is
used in advanced cases. Although quick to metastasize, this variant
shows a favorable response to chemotherap Cytology Because the diagnosis of large cell carcinoma is
made after the exclusion of squamous, glandular, or small cell
components, it is often classified as a non–small cell carcinoma
on small tissue specimens such as transbronchial biopsies and
cytological specimens. Cytological smears show an undifferentiated
carcinoma without squamous, glandular, or small cell
features. Smears are usually cellular and composed of both
single cells and syncytial aggregates. Cells are large with high
N/C ratios, large nuclei with prominent or multiple nucleoli
in a background of necrosis.
Immunohistochemistry of Large Cell Lung Carcinoma
The immunohistochemical staining properties of LCLC are
listed in Table 22.3. In general, they are similar to other forms of
NSCLC with the exception of a higher level of expression of proliferation
markers, reflecting the rapid growth of these tumors.
UNCOMMON BUT SIGNIFICANT VARIANTS
OF NON–SMALL CELL LUNG CARCINOMA
Several histological variants of NSCLC are significant because
of their distinct morphology and prognosis. The most prominent
among these variants are basaloid carcinoma and pleomorphic
carcinoma.
Basaloid Carcinoma This variant histology may be
found admixed with other forms of non–small cell carcinoma
or as the sole cell type in a subgroup of lung carcinomas.
Basaloid histological features include lobular growth
of relatively small cells with dense nuclei, inconspicuous
nucleoli, scant cytoplasm, a high mitotic rate, and peripheral
palisading. 119 Misinterpretation of these tumors as SCLC has
been described in fine-needle aspirations. 120,121 Small cell variant
of squamous carcinoma is also distinguished from undifferentiated
small cell carcinoma by nuclear features including
prominent nucleoli and a coarse clumping of the chromatin.
In doubtful cases, immunohistochemical stains for neuroendocrine
markers may be applied (see succeeding discussion).
The reported frequency is about 6% of all lung cancers. 119
The reported prognostic significance of basaloid histology has
been inconsistent with one study finding reduced actuarial
5-year survival for basaloid tumors in comparison to poorly
differentiated squamous tumors 122 but a second similar-sized
study finding similar survival for the two tumor types. 123
Since these tumors are rare, additional studies, perhaps through
a multicenter registry, will be necessary to better characterize
their behavior.
Carcinomas with Pleomorphic, Sarcomatoid, or
Sarcomatous Elements These carcinomas have been recognized
under various names for many years including spindle
cell carcinoma, giant cell carcinoma, pleomorphic carcinoma,
and carcinosarcoma. This category consists of tumors that are
composed exclusively of sarcoma or pleomorphic tumor cells or
of tumors that contain a component of sarcomatoid or pleomorphic
cells along with tumor of a more usual histological type. In
the most recent WHO classification, 1 these tumors are grouped
in a single diagnostic category. These tumors are uncommon
and usually reported as single cases but two larger series have
also been published. 124,125 The median survival in these series
is 10 months.
Sarcomatoid tumor histology is characterized by the presence
of spindle areas that resemble sarcoma. 124,125 The sarcomatous
element in this variant type may contain muscle, bone,
or cartilage as well as undifferentiated spindle cells. 124,125 There
also may be mixtures of epithelial tumor and sarcomatous components,
referred to as carcinosarcoma. The giant cell variant of
the category consists of highly pleomorphic cells that form multinucleated
giant cells, usually accompanied by a heavy inflammatory
infiltrate. In most cases, these tumors have biomarker
profiles similar to those of other lung tumors, expressing CK7
and TTF-1. 125 However, in approximately 25%, either one or
the other or both of these biomarkers is (are) absent and these
negative tumors tend to be those with the most sarcomatous
histological appearance.
The biological significance of this category of tumor
has been emphasized by the recent description of the stromal
molecular and cellular properties in tumors that are
otherwise considered epithelial. This pattern of differentiation
has been referred to as epithelial mesenchymal transition
(EMT). Properties associated with EMT include change in
cell culture characteristics from the sheetlike pattern of epithelial
cells to a more single cell infiltrative stromal pattern
of growth. 126 This morphological change is accompanied by
increased expression of vimentin intermediate filament and
the transcription factor ZEB1 and by reduced expression of
the adhesion molecule E-cadherin, the transcription factor
SNAIL, and EGFR. 127 Such molecular changes are most
evident in tumors that exhibit elements of sarcomatoid differentiation
but poorly differentiated tumors without sarcomatous
elements may also lose expression of E-cadherin.
Loss of E-cadherin imparts a poor prognosis independent of
stage 128 and resistance to EGFR blockade. 77,106,127,129–131 It
seems likely that the loss of E-cadherin represents part of a
continuum of dedifferentiation that at its most extreme is
reflected in the pleomorphic tumor category. This category
will require unique therapeutic consideration, especially as
targeted drugs become increasingly available for tumors with
specific molecular phenotypes.