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From: J on 22 Jul 2008 01:36
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Neuroendocrine Morphology: Essential Radiologic and Pathologic Features
Teri J. Franks, MD; Jeffrey R. Galvin, MD

From the Departments of Pulmonary and Mediastinal Pathology (Dr Franks)
and Radiologic Pathology (Dr Galvin), Armed Forces Institute of Pathology,
Washington, DC; and the Departments of Diagnostic Radiology and Internal
Medicine, Division of Pulmonary/Critical Care Medicine, University of
Maryland School of Medicine, Baltimore (Dr Galvin)

Accepted December 17, 2007


Context.�Tumors with neuroendocrine morphology are a distinct
subset of lung neoplasms sharing characteristic histologic,
immunohistochemical, ultrastructural, and molecular features.

Objective.�To review the current histologic classification and the
diagnostic criteria for the major categories of neuroendocrine tumors of
the lung.

Data Sources.�Published classification systems from the World
Health Organization and pertinent peer-reviewed articles indexed in PubMed
(National Library of Medicine) form the basis of this review.

Conclusions.�Accurate classification of the neuroendocrine tumors
of the lung requires knowledge of specific criteria separating the major
categories, which is essential for determining prognosis and treatment.

Tumors with neuroendocrine morphology are a distinct subset of lung
neoplasms that share specific morphologic, immunohistochemical,
ultrastructural, and molecular characteristics. The major categories of
morphologically identifiable neuroendocrine tumors include typical
carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine
carcinoma (LCNEC), and small cell carcinoma of the lung (SCLC) (Table 1 ).
Although these tumors share a variety of characteristics, widely varying
prognosis and response to therapy necessitated placement in separate
categories within the World Health Organization classification.1,2
However, it is easiest to conceptualize this group as a spectrum of
malignancy ranging from low-grade TC, to intermediate-grade AC, to the 2
high-grade malignancies, LCNEC and SCLC. These 4 carcinomas are
distinguished from nonneuroendocrine lung carcinomas on light microscopy
by their display of neuroendocrine morphology including organoid nesting,
rosette formation, peripheral palisading of tumor nests, and trabeculae
and on immunohistochemistry by reactivity with neuroendocrine markers.
Separation within the neuroendocrine tumors rests primarily on mitotic
rate and the presence or absence of necrosis, and, in the case of
separating LCNEC from SCLC, cell morphology (Table 2 ).

Although the neuroendocrine tumors of the lung are separated into 4
categories and form a spectrum of malignancy, TC and AC as a group share
interesting contrasts to LCNEC and SCLC. Typical carcinoid and AC occur in
a younger patient population than LCNEC and SCLC; essentially all patients
with LCNEC and SCLC are smokers, whereas approximately one third of TCs
and ACs occur in nonsmokers; in contrast to LCNEC and SCLC, TC and AC are
frequently associated with neuroendocrine cell hyperplasia with or without
tumorlets; and other major histologic subtypes of lung carcinoma occur in
combination with LCNEC and SCLC but not with TC and AC.1 Genetic
abnormalities in p53,3,4 cyclin D1,5 Bcl-2/Bax,6 and RB loss and loss of
heterozygosity at 3p,7,8 occur in a higher percentage of LCNECs and SCLCs
than TCs and ACs further distinguishing the 2 high-grade malignancies from
the 2 carcinoids.

Staging, treatment, and survival vary widely among the 4 neuroendocrine
lung tumors, thus accurate histologic classification is essential. The TNM
classification is the most widely used staging system for TC, AC, and
LCNEC; however, it is generally not applied to SCLC as it is a poor
indicator of survival. Instead, SCLC is staged as limited or extensive
disease (Table 3 ). There is essentially equal distribution of limited and
extensive disease at diagnosis.9 Typical carcinoid and AC are treated
surgically, most often by lobectomy or pneumonectomy depending on location
of the tumor. Whether surgery and/or chemotherapy is the optimal treatment
for LCNEC is controversial and has yet to be established. Chemotherapy
remains the primary treatment for SCLC. The overall 5-year survival rates
for TC, AC, LCNEC, and SCLC after stratification for stage are
approximately 90%, 60%, 20%, and 3.5% respectively.9�11

TYPICAL AND ATYPICAL CARCINOID Return to TOC

Carcinoids comprise 1% to 2% of all lung neoplasms and are the most common
lung tumor of childhood.12 In large studies, men and women are affected
equally, with a mean age of approximately 45 years.13�15 Symptoms vary
with location. Central lesions produce early symptoms including cough,
wheezing, dyspnea, and hemoptysis because of airway obstruction, whereas
peripheral lesions are frequently discovered incidentally on chest imaging
studies in asymptomatic patients.16,17

Eighty-five percent of carcinoids are located centrally within mainstem
and lobar bronchi18 and present with evidence of bronchial obstruction as
the most common radiologic finding (Figure 1 ). Carcinoids manifest as
well-demarcated, round to oval, hilar or perihilar nodules (less than 3
cm) or masses (3 cm or greater). Airway obstruction is typically complete
resulting in volume loss and atelectasis, obstructive pneumonia, or mucoid
impaction distal to the tumor. Calcification is common. Tumors often show
substantial contrast enhancement because of their rich vascularity.
Although AC tends to be larger and have a slightly greater tendency to be
peripheral,19 there is substantial overlap and TC and AC are
radiographically indistinguishable.20

Grossly, carcinoids are well-demarcated masses with tan-yellow or red cut
surfaces depending on the extent of vascularity. Necrosis and hemorrhage
may be present in AC. Size varies from 0.5 cm to 10 cm, with mean
diameters of central lesions greater than those in the periphery and AC
greater than TC.21 Central lesions tend to have a large endobronchial
component, but varying extension outside the bronchial wall can result in
the bulk of tumor residing in the surrounding lung parenchyma (Figure 2 ).

Histologically, carcinoids are composed of uniform polygonal, spindle
cells, and/or oxyphilic cells with moderate amounts of cytoplasm, fine
nuclear chromatin, and inconspicuous nucleoli. Carcinoids are typically
histologically heterogeneous displaying a spectrum of growth patterns.
Organoid, rosette, palisading, and trabecular patterns of growth are
common, but papillary, sclerosing, follicular, or glandular patterns also
occur (Figure 3 ). Mitotic rate and presence or absence of necrosis
distinguish TC from AC; TC has fewer than 2 mitoses per 2 mm2 (10
high-power fields) without necrosis, whereas AC has 2 to 10 mitoses per 2
mm2 (10 high-power fields) and/or necrosis. Pleomorphism and nuclear
atypia can be prominent but are unreliable features for separating the 2
carcinoids.11 The majority of carcinoids are immunoreactive with
pancytokeratin, and neuroendocrine differentiation can be confirmed with
the neuroendocrine markers chromogranin, synaptophysin, and CD56 (N-CAM).

There are several pitfalls in this setting. Size alone distinguishes
tumorlets from the carcinoids, the former are arbitrarily defined as less
than 0.5 cm and the latter 0.5 cm or greater, so that on limited material
this distinction cannot necessarily be made. On small specimens, such as
transbronchial or endobronchial biopsies or needle biopsies, separation of
TC from AC is possible if necrosis or a sufficient number of mitoses are
present; however, a resected specimen is typically required to make this
determination. Because carcinoids often present a significant
endobronchial component, surface erosions are common and the endobronchial
portion is readily accessible to the bronchoscopists' forceps and needles.
Care must be taken not to misinterpret necrosis from erosion and biopsy
sites as tumor necrosis; if present, necrosis changes the diagnosis of TC
to AC and a worse prognosis. Necrosis in AC is described as punctate,
usually occurring in the center of tumor nests (Figure 4 ), rather than
diffuse along the surface as in erosion or linear from instrumentation.
Because the nuclear morphology of carcinoid is similar to small cell
carcinoma�fine chromatin with inconspicuous nucleoli�care must also be
taken in small biopsies to evaluate the volume of cytoplasm and number of
mitoses to avoid misdiagnosis. Even in small biopsies, the scant volume of
cytoplasm and high mitotic rate of small cell carcinoma are usually
evident.

LARGE CELL NEUROENDOCRINE CARCINOMA Return to TOC

Large cell neuroendocrine carcinoma accounts for approximately 3% of lung
cancers,22 and patients are typically male cigarette smokers in the sixth
decade of life.23 Symptoms produced by the primary tumor are similar to
other non�small cell lung carcinomas and vary with location.

The radiologic findings in LCNEC are also indistinguishable from those of
other non�small cell lung carcinomas. Approximately 80% of LCNECs appear
as peripheral nodules or masses; the remainder form central masses
frequently contiguous with the mediastinum.24,25 Tumors are well-defined
and lobulated with an increasingly heterogeneous pattern of enhancement in
larger examples (Figure 5 ).

Large cell neuroendocrine carcinoma is similar to other non�small cell
carcinomas on gross examination. Histologically, LCNEC is composed of
cytologically malignant large cells demonstrating neuroendocrine
morphology, most commonly rosette formation and peripheral palisading of
tumor nests. However, these features are often subtle, making distinction
from non�small cell lung carcinoma difficult. In some cases, rosettes are
the only histologic marker of neuroendocrine differentiation. Tumor cells
show cytologic features of non�small cell lung carcinoma including large
cell size, low nuclear-cytoplasmic ratio, vesicular or fine chromatin, and
frequent nucleoli. Large cell neuroendocrine carcinoma may have fine
nuclear chromatin and lack nucleoli but qualify because of large cell size
and abundant cytoplasm.1 Mitotic counts are defined as greater than 10/2
mm2 (10 high-power fields); however, the median count is 70/2 mm2.1
Necrosis is usually present, often in large zones. Cell size, cytoplasmic
volume, and presence of nucleoli facilitate separation from SCLC (Figure 6
). The histologic diagnosis of LCNEC requires fulfillment of 2 criteria:
demonstration of neuroendocrine morphology by light microscopy and
positive immunohistochemical staining for 1 or more neuroendocrine markers
(other than neuron-specific enolase).1,2 Chromogranin, synaptophysin, and
CD56 (N-CAM) are the most sensitive and specific neuroendocrine markers.
One positive marker is sufficient for diagnosis if the staining is clear
cut2; however, most often several markers will be reactive.

Ten percent to 20% of non�small cell lung cancers (squamous cell,
adenocarcinoma, and large cell carcinoma) demonstrate neuroendocrine
differentiation by immunohistochemistry but not morphologically and should
be classified by conventional subtype with neuroendocrine differentiation
noted.1 Whether these tumors have better or worse survival or are more or
less responsive to chemotherapy than non�small cell lung cancers without
neuroendocrine differentiation is controversial; studies report better,
worse, and no difference in prognosis and response to chemotherapy.2

SMALL CELL CARCINOMA Return to TOC

Approximately 20% of lung cancers are SCLCs.26 Similar to LCNEC, most
patients with SCLC are older male smokers. The central location of most
tumors gives rise to the common clinical manifestations of cough, dyspnea,
and hemoptysis. Invasion of mediastinal structures may result in
dysphagia, hoarseness, and superior vena cava syndrome.

Small cell carcinoma is relatively distinctive on imaging. Approximately
95% of tumors are central and related to proximal airways, particularly
lobar and main bronchi; less than 5% arise in the peripheral lung without
obvious airway association.27 Central tumors are poorly demarcated.
Metastases to hilar lymph nodes and mediastinal involvement secondary to
metastases to mediastinal lymph nodes and/or direct invasion from a
contiguous mass are almost invariably present (Figure 7 ). Peripheral SCLC
is radiologically indistinguishable from other lung neoplasms.

Grossly, SCLC characteristically spreads along airway submucosa and
peribronchovascular connective tissue. Subsequent extension into the lung
parenchyma results in an expanding mass that obliterates airways and
vessels by external compression rather than intraluminal growth. In
contrast to squamous cell carcinoma, endobronchial growth is uncommon in
SCLC.

Histologically, SCLCs are composed of small cells, defined as less than
the size of three small resting lymphocytes, with scant cytoplasm, fine
nuclear chromatin, and inconspicuous or absent nucleoli.1 Although SCLC
can display organoid nesting, rosettes, peripheral palisading of tumor
nests, and trabeculae, sheetlike growth with rosettes or absent
neuroendocrine morphology are more common. Cell borders are indistinct,
spindle morphology may be striking, and molding of tumor cells may be
present. The mitotic rate is high with a median of 80/2 mm2.1 Good quality
hematoxylin-eosin�stained sections are essential for evaluation. In
suboptimal histologic sections, bubble artifact gives cell nuclei the
appearance of having vesicular chromatin, which can lead to an erroneous
diagnosis of non�small cell carcinoma (Figure 8 ).

Small cell carcinoma is immunoreactive with pancytokeratin, cytokeratin 7,
chromogranin, synaptophysin, CD56, and thyroid transcription factor 1 in
most cases; however, up to 10% of tumors are negative for all
neuroendocrine markers.28 In small biopsies, especially those with
extensive crush artifact, separation of SCLC from lymphoma on
hematoxylin-eosin staining alone can be difficult; pancytokeratin and/or
CD45RB (leukocyte common antigen) stains will usually resolve the problem.
Merkel cell carcinoma, in cervical lymph node biopsies, and primitive
neuroectodermal tumors are also pitfalls in diagnosis because of their
histologic similarity to SCLC. In contrast to SCLC, Merkel cell carcinoma
is cytokeratin 20 positive, and cytokeratin 7 and thyroid transcription
factor 1 negative, whereas primitive neuroectodermal tumor is CD99
positive, is less mitotically active, and the majority are pancytokeratin
negative.

In conclusion, the identification of neuroendocrine tumors of the lung is
a step-wise process. First, tumors must be recognized as neuroendocrine by
the presence on light microscopy of neuroendocrine morphology including
organoid nesting, rosette formation, peripheral palisading of tumor nests,
and trabeculae. Once a tumor is considered to be neuroendocrine,
separation into the 4 major neuroendocrine categories is achieved using
mitotic rate and the presence or absence of necrosis, and in the instance
of separating LCNEC from SCLC, cell morphology. The diagnosis of LCNEC
requires the presence of both neuroendocrine morphology by light
microscopy and demonstration of neuroendocrine differentiation by
immunohistochemistry. Tumors of the lung with neuroendocrine
differentiation have widely varying prognosis and response to therapy;
thus, accurate histologic classification is essential.

References Return to TOC

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