DEFINITION MIXED SMALL CELL AND NON–SMALL CELL CARCINOMA

It is of interest that a large proportion of small cell carcinomas
contain a component of non–small cell tumor. These tumors
include large cell carcinoma, adenocarcinoma, and squamous
carcinoma. In a recent review of 100 small cell carcinomas,
Nicholson et al. 171 found 72 pure small cell carcinomas and
28 combined small cell carcinomas. Sixteen cases were combined
with large cell carcinoma, nine with adenocarcinoma,
and three with squamous cell carcinoma.
BRONCHIAL CARCINOID, ATYPICAL
CARCINOID AND LARGE CELL
NEUROENDOCRINE CARCINOMA
The term carcinoid was originally coined in 1907 to describe a
subset of gastrointestinal epithelial tumors that were less aggressive
than the conventional gastrointestinal carcinoma and were
therefore designated carcinoid tumors rather than carcinoma . 172
It was subsequently demonstrated that similar tumors existed
in the lower respiratory tract. 173 Currently, these tumors together
with SCLC and LCNEC are regarded as neuroendocrine
and are considered part of a continuum. Carcinoid tumor is
the lowest grade and least aggressive of this group and SCLC
is the highest grade and most aggressive. 174,175 This category
also includes atypical carcinoid, which characteristically has an
elevated mitotic rate in comparison to typical carcinoid and behaves
more aggressively with a metastatic rate of approximately
50%. Finally, LCNEC is an aggressive, high-grade tumor that
was first described in 1991 175 as an undifferentiated tumor
that is intermediate in morphological features and prognosis
between atypical carcinoid and SCLC.
Typical Carcinoid Tumor Typical carcinoid tumors may
arise in the either central or peripheral airways. They usually
have strikingly different macroscopic features in the two locations.
The central airway tumors are relatively large (mean
diameter 3 cm) 176 and grow as endobronchial masses that may
obstruct the large bronchi (Fig. 22.9). The secretory products
of these tumors also may induce swelling of adjacent tissues
that augments the obstruction caused by the tumor itself.
These tumors may extend into the bronchial wall but such
infiltration does not necessarily imply aggressive growth and
is not a criterion for atypical carcinoid. The sectioned surface
of carcinoid tumor is usually gray and homogeneous. The
histological features that distinguish carcinoid tumors from
NSCLC are relative uniformity of the tumors cells, abundant
grayish granular cytoplasm, lack of tumor cell necrosis, and
round to oval nuclei with finely granular (salt and pepper)
nuclear chromatin and inconspicuous nucleoli. Carcinoid cells
form small clusters without true gland formation in a pattern
that is variously described as organoid or insular. Cells and nuclei
are frequently oriented perpendicularly to the basement
membrane, forming palisading or rosettelike patterns. To distinguish
slow-growing typical carcinoids from more aggressive
tumors, the diagnosis is limited to those tumors with 2 mitoses
per 2 mm 2 ( 10 hpf ) and no necrosis. 60
Carcinoid tumors may also grow in the peripheral
lung. Minute ( 5 mm) peripheral carcinoid tumors, referred
to as tumorlets , 177 are frequent incidental findings
in lungs resected for other lung diseases and are benign.
Larger carcinoid tumors may also occur in the peripheral
lung. The uniform cellular appearances of the central airway
tumors are recapitulated in the peripheral tumors with
the exception that tumor cells are found in the bronchioles
and in some cases, the tumors have a spindled appearance
(spindle cell carcinoid tumor 178 ).
Symptomatic carcinoid tumors represent 1% to 2% of all lung
carcinomas and survival at both 5 and 10 years is 87%. 174,179
Atypical Carcinoid A mitotic rate of 2 to 10 per 2 mm 2
and foci of necrosis are the features that separate atypical from
typical carcinoid (Fig. 22.9) as first defined by Arrigoni et al. 180
In contrast to the low mortality of typical carcinoid,
atypical carcinoid tumors have a survival rate of 50% to
60% at 5 years and 35% at 10 years, a mortality effect that
remains significant in multivariate analysis. 174,181 Patients
with atypical carcinoid are reported to have higher tobacco
smoke exposure than the general population or patients with
typical carcinoid. 182 A smoking association is supported by
an increase in the prevalence of smoking-associated genetic
changes including LOH and p53 mutation in atypical carcinoid
in comparison to typical carcinoid. 183
Large Cell Neuroendocrine Carcinoma In the
LCNEC, necrosis is also frequently present and mitotic
rate exceeds 10 mitoses per 2 mm 2 areas. Cells often retain
a neuroendocrine appearance with organoid nesting, trabeculae,
rosettelike structures, and peripheral palisading 175
(Fig. 22.9). Nuclei may exhibit the fine granularity seen
in SCLC but there are often more conspicuous nucleoli.
Immunostains for neuroendocrine markers may or may
not be positive and are not necessary for diagnosis when
neuroendocrine differentiation is evident. Conversely, the
diagnosis of LCNEC in an undifferentiated large tumor
may be based purely on immunohistochemical staining results
(Table 22.3). LCNEC is distinguished from SCLC on
the basis of the aforementioned features as well as cell size
21 microns (3 lymphocyte diameters).
The incidence of LCNEC carcinoma is approximately
3% of all primary pulmonary malignancies 184,185 and is
strongly associated with smoking history. 186 It is generally
thought that LCNEC carries a worse prognosis than
other non–small cell carcinomas. 179,187 Five-year survival
for this tumor from several studies varies from 15% 179 to
27%, 174,186 and 10-year survival is reported at 9%. 174,187
Another study of 87 cases of LCNEC reported significantly
worse survival for stage I patients 185 but overall 5-year survival
was not significantly different from an overall 5-year
survival of or the NSCLC at 57%. Although currently
treated as NSCLC, the prognosis for LCNEC approaches
that of small cell carcinoma, and treatment options may
change in the future. 188,189
Cytology of Carcinoid Tumor and Large Cell Neuroendocrine
Carcinoma Although most carcinoid tumors
are centrally located, their cytologic features are better seen on
fine-needle aspiration specimens than in sputum. Smears show
small uniform cells with central to eccentric round nuclei with
smooth nuclear outlines. There is no molding as seen with highgrade
neuroendocrine carcinomas. A minority of carcinoid tumors
can have spindle-shaped cells. Cytologically, atypical carcinoids
show more pleomorphism, atypia, higher N/C ratios,
more irregular membranes, and coarser chromatin than typical
carcinoids. Cells are arranged as single cells and syncytial aggregates,
and necrosis may be present 190 ; however, these features are
only suggestive and tissue is required for a definitive diagnosis.
Suggested cytological criteria for LCNEC include flattened
three-dimensional groups of cells with peripheral palisading,
moderate to large cells, some molding and crush artifact,
prominent nucleoli, mitoses, necrosis, and positive neuroendocrine
markers. 191,192 Distinction between SCLC and NSCLC
may be difficult on cytological examination 193 unless enough
material is available for a cell block to evaluate architectural
features and immunohistochemical biomarker expression.
Immunohistochemisty of Carcinoid Tumor and Large
Cell Neuroendocrine Carcinoma As mentioned previously,
expression of immunohistochemical markers is currently
one of the two defining criteria of neuroendocrine tumors.
Table 22.3 lists antibodies that distinguish among neuroendocrine
tumor types. Antibodies that are most generally useful in
the evaluation of neuroendocrine tumors include NCAM, synaptophysin,
and chromogranin. 194–201 LCNEC frequently expresses
one or more neuroendocrine markers. 153,202 However,
staining tends to be more focal and weaker than that observed
with SCLC or carcinoid tumor (Table 22.3). In a small subset
of LCNEC, immunostains for these markers are negative and
diagnosis is made on the basis of histology alone.
Electron microscopy has, in the past, been useful in characterizing
neuroendocrine tumors but has largely been replaced
by less expensive and often more informative immunohistochemical
tests.
Cell of Origin: Small Cell Lung Carcinoma and
the Neuroendocrine Tumor Hypothesis Since
the original description of SCLC, the cell of origin has
been the subject of much speculation. In the 1960s, the hypothesis
was advanced that these tumors were derived from
Kulchitsky (K) cells that are scattered along the airway surfaces.
203 K cells were considered to be a part of a dispersed
neuroendocrine system. 204 These cells were thought to be
derived from neural crest and thus separately derived from
the rest of the lung. However, the neuroendocrine cells were
later shown to be derived locally. 205 Although K cells populate
the bronchial epithelium at a density of approximately
one cell per millimeter, these cells are infrequently observed
in premalignant conditions. Moreover, SCLC arises in a milieu
similar to that of non–small cell central airway lesions
including widespread squamous metaplasia and dysplasia.
This, together with the frequent combination of small cell
and non–small cell elements in lung carcinomas, suggests
that the small cell tumors may have the same progenitor cells
of origin as NSCLC.
The hypothesis that tumors with neuroendocrine
properties should be grouped into a single category is not
universally accepted 206 for several reasons. First, a large
proportion of lung carcinomas have mixed nonneuroendocrine
and neuroendocrine properties. This is particularly
evident in molecular profiling studies where otherwise
unremarkable adenocarcinomas have been shown to express
clusters of genes that are thought to reflect neuroendocrine
differentiation. 96,97,207 Adenocarcinomas having
this gene expression profile have a worse prognosis than
other adenocarcinomas. Second, many of the markers that
are regarded as neuroendocrine markers are expressed in
a variety of cells in addition to neuroendocrine cells. 206
Third, neuroendocrine markers including NCAM are expressed
during embryonic development of the lung. 208 For
example, 209 gastrin-releasing peptide signaling has been to
shown to determine airway branching in the embryonic
mouse lung. 210 Expression of neuroendocrine biomarkers
in LCNEC could be regarded as evidence of dedifferentiation
to a more primitive developmental stage rather than
neuroendocrine differentiation.
At the present time then, expression of neuroendocrine
biomarkers may be regarded as an interesting but not yet fully
understood property of lung carcinomas that may be prognostically
important within specific histological categories.
Moreover, expression of neuroendocrine-associated genes may
provide therapeutic targets but does not necessarily indicate
ontological relationships among tumors. The biological rationale
for grouping diverse lung tumors into a single neuroendocrine
diagnostic category is problematic and this grouping
has not yet been unequivocally proven to be clinically relevant.
It may yet prove to be more useful to annotate conventional
histological categories with biomarker expression data rather
than retain the neuroendocrine designation to refer to such a
divergent group of tumors.