NEUROENDOCRINE NEOPLASMS

Pulmonary neuroendocrine tumors comprise approximately
20% of lung malignancies. 42 According to the most recent
World Health Organization classification, they are histologically
divided into a three-tier, four-category system including
low-grade (typical carcinoid), intermediate-grade (atypical
carcinoid), and high-grade (small cell carcinoma and large
cell neuroendocrine carcinoma) tumors. 22 Overall, all tumors
have characteristic neuroendocrine architecture including organoid,
nesting, trabecular, insular, palisading, ribbon, papillary,
cord, or rosettelike patterns. The distinction among the
spectrum of neuroendocrine tumors is largely based on the
number of mitoses and presence/absence of necrosis. Typical
carcinoids have less than two mitoses per 2 mm 2 and no
necrosis; atypical carcinoids have between 2 and 10 mitoses
per 2 mm 2 and/or necrosis; large cell neuroendocrine carcinomas
and small cell carcinomas have greater than 10 mitoses
per 2 mm 2 and necrosis. Although the diagnostic criteria are
primarily based on histological features, the architectural patterns
and nuclear features are often reflected in cytological
specimens. However, application of these criteria to neuroendocrine
tumors in small biopsy specimens 42 and cytological
specimens can be challenging.
Typical and Atypical Carcinoids
Typical Carcinoid Typical carcinoid (Fig. 18.5) comprises
approximately 1% to 2% of pulmonary neoplasms, 42 and it
is not associated with smoking. Typical carcinoid occurs at
any age, with the mean age being 50 years. 42 Carcinoid aspirates
are usually hypercellular and demonstrate loose cell
clusters and single cells. 43 The cell groups often form syncytia,
rosettes, 43 and trabeculae. Clusters may also be associated
with a prominent streaming, arborizing capillary network in
a hemorrhagic background, 44 a feature characteristic of typical
and atypical carcinoids but not high-grade neuroendocrine
carcinomas. 45–47 Papillary architecture is also seen in some
carcinoids. 48,44 Single cells are also frequently seen in aspirates
of carcinoids. Overall, the cells can have eccentrically placed
nuclei with faint eosinophilic granular cytoplasm imparting
a plasmacytoid appearance, or they may be stripped of their
fragile cytoplasm and show bare nuclei. 44 Nuclei are relatively
uniform/monomorphic and round with smooth contours.
Spindle-shaped cells are also present in spindle cell carcinoids.
Slightly larger and pleomorphic cells can also be observed in
carcinoids. 47 The nuclei have fine granular chromatin and inconspicuous
nucleoli. Rare intranuclear inclusions have also
been described. 44 No obvious nuclear molding, necrosis, or
mitoses are observed. In addition to the aforementioned characteristics,
carcinoids may also have oncocytic, acinic cell,
signet ring cell, and melanocytic features, but these traits have
no impact on prognosis. 42
Atypical Carcinoids Atypical carcinoid (Fig. 18.6) patients
have a mean age of 54 years 42 and tend to be nonsmokers.
Most of the cytology literature describing atypical carcinoid
predates the current World Health Organization’s classification
of neuroendocrine tumors. Despite the modification, the
overall cytological features of atypical carcinoid are similar to
typical carcinoids with few minor exceptions. The neoplastic
cells may be slightly more pleomorphic and larger. In addition,
atypical carcinoids are associated with mitoses and/or necrosis,
similar to their histological counterparts.
Immunohistochemistry Typical carcinoid stains with
cytokeratin but a minority may be negative. Staining with
neuroendocrine markers (chromogranin, synaptophysin,
and CD56) is often strong. TTF-1 staining is variable with
some series reporting no staining, 49 and others demonstrating
expression in approximately one third of typical carcinoids.
50 Atypical carcinoid, like typical carcinoid, stains with
cytokeratin. Expression of neuroendocrine markers is relatively
less intense, 42 but TTF-1 staining is more common in atypical
carcinoids. 50
Differential Diagnosis Carcinoid and atypical carcinoid
can be challenging to distinguish from each other as well as
other neuroendocrine neoplasms. Typical and atypical carcinoids
can be difficult to differentiate from each other in a
limited aspirate sample where mitoses and necrosis cannot be
thoroughly assessed. A typical carcinoid may be misclassified
as an atypical carcinoid following necrosis that may occur during
a prior fine-needle aspiration. 42 Furthermore, presence of
some large and pleomorphic cells may suggest a high-grade
neuroendocrine tumor; however, a diagnosis of small cell and
large cell neuroendocrine carcinoma should be avoided in
the absence of necrosis and brisk mitotic activity. 47 Ki67 and
Pax-5 immunostains may also be helpful; often 50% staining
favors a high-grade neuroendocrine neoplasm. 51,52
The monomorphism of carcinoid and prominent papillary
pattern may be confused with sclerosing hemagioma. 48,44
Sclerosing hemangiomas tend to have hyalinized stromal
tissue, foamy and/or hemosiderin-laden macrophages, two
cell populations, and stippled chromatin 40 ; also, neuroendocrine
markers are negative. Carcinoids can also mimic metastatic
breast carcinoma, 12 especially those with neuroendocrine
features. 53 Comparison with the primary breast carcinoma
histology and immunostains (TTF-1, estrogen receptor and
progesterone receptor, BRST-2) can be helpful in determining
the primary.
Small Cell Carcinoma Small cell carcinoma (Fig. 18.7)
comprises approximately 20% to 25% of lung carcinomas. 42
Small cell carcinoma, unlike carcinoid, is related to tobacco use
and occurs in slightly older patients with a median age of 62
years. The significance of separating small cell carcinoma from
non–small cell carcinoma is well established. Similarly, the distinction
between small cell carcinoma and other pulmonary
neuroendocrine tumors is also critical; this can be challenging
because the diagnosis is often made on small biopsies and cytological
specimens.
Aspirates of small cell carcinoma show clusters or linearly
arranged cells with prominent nuclear molding and single
cells with high nuclear:cytoplasmic ratios, round, ovoid, and
spindle-shaped cells with scant basophilic cytoplasm. In the
surgical pathology literature, the cells are typically less than
the diameter of three small resting lymphocytes. 54 The nuclei
have fine “salt and pepper” stippled chromatin with absent/
inconspicuous nucleoli. The background demonstrates nuclear
smearing/crush artifact, necrosis, and apoptosis. Paranuclear
blue inclusions, which are spherical light to dark blue structures
that indent the nucleus, 55 are often associated with small
cell carcinomas and seen primarily on air-dried smears. 56
Immunohistochemistry Neuroendocrine markers including
chromogranin, synaptophysin, and NCAM (CD56) can
also be helpful, but they stain approximately up to two third of
cases. 54 TTF-1 expression has been described in up to approximately
95% 42 of small cell carcinomas of the lung; however, it
also stains small cell carcinomas of extrapulmonary origin and
non–small cell carcinomas
Differential Diagnosis In surgical specimens, cellular dyscohesion
is also noted in rare cases of small cell carcinoma. 54
An aspirate from such areas as well as the small size 57 of lowgrade
lymphomas may lead to an erroneous diagnosis of lymphoma.
Unlike carcinomas, lymphomas are associated with
lymphoglandular bodies in the background. Confirmation
of epithelial origin with a cytokeratin stain is valuable too.
Paranuclear blue inclusions, often associated with small cell carcinoma,
have also been described in minority of rhabdomyosarcomas,
56 non–small cell carcinomas, 55 and lymphomas. 55
Large Cell Neuroendocrine Carcinoma Large cell
neuroendocrine carcinomas predominate in smokers and men,
and the median age of presentation is approximately 63 years. 58
Histologically, large cell neuroendocrine carcinomas have the
typical neuroendocrine architecture. They also have tumor necrosis
and high mitotic rate like small cell carcinomas. Unlike
the latter, however, large cell neuroendocrine carcinomas on
histological sections have large tumor cells with low nuclear:
cytoplasmic ratio, eosinophilic cytoplasm, coarse chromatin,
and frequent nucleoli. 59 These features are recapitulated in
cytological specimens. 60–62 The aspirates show neoplastic cells
in flattened three-dimensional sheets with peripheral palisading
and single cells comprised of pleomorphic large cells with
moderate to scant cytoplasm, large nuclei with thick membranes
and coarse or finely granular chromatin, prominent
nucleoli, focal nuclear molding, and crush artifact. 60
Immunohistochemistry By definition, large cell neuroendocrine
carcinomas should express at least one of the neuroendocrine
markers (chromogranin, synaptophysin, CD56).
Approximately 50% of large cell neuroendocrine tumors express
TTF-1. 49 These tumors typically do not express high–molecular
weight cytokeratin. 49,63
Differential Diagnosis Given the brisk mitotic activity
and necrosis, large cell neuroendocrine carcinoma could be
mistaken for small cell carcinoma. The cell size (3 to 5 times
the size of a red blood cell in large cell neuroendocrine carcinoma
and 1 to 2.5 times the size of a red blood cell in small
cell carcinoma) and distinct nucleoli (in large cell neuroendocrine
carcinoma) can be used to distinguish the two entities. 61
A few prominent nucleoli can be seen in small cell carcinoma,
and the diagnosis should be based on the cytological features
of the predominant cell type.
Combined Small Cell Carcinoma Combined small
cell carcinoma has small cell carcinoma and non–small cell
carcinoma, which may constitute large cell carcinoma, adenocarcinoma,
squamous cell, spindle, or giant cell carcinoma. 54
Prognosis and Treatment The subclassification of neuroendocrine
tumors is important because it impacts prognosis
and treatment. Statistically significant differences in survival
have been reported between typical/atypical carcinoids and
large cell neuroendocrine carcinomas 22 ; however, a significant
difference in survival has not been identified between large cell
neuroendocrine carcinoma and small cell carcinoma. 64
Large Cell Carcinoma Large cell carcinoma is a diagnosis
of exclusion of poorly differentiated carcinoma without
evidence supporting squamous, glandular, or neuroendocrine
components. The cells have large cells with vesicular nuclei
and prominent nucleoli. 12 Ultrastructurally, there is evidence
of minimal differentiation toward squamous cell carcinoma or
adenocarcinoma.