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34BetaE12 expression along the whole spectrum of neuroendocrine
proliferations of the lung, from neuroendocrine cell hyperplasia to
small cell carcinoma.Histopathology.
2003 Feb;42(2):156-66.
AIMS:
Monoclonal antibody 34betaE12 (Ck34betaE12) recognizes a set of
cytokeratins (1, 5, 10, 14) expressed in normal stratified squamous
epithelium. We have recently reported its expression in squamous cell
carcinoma and basaloid carcinoma, in contrast to large cell
neuroendocrine carcinoma, an entity with overlapping morphological
features with basaloid carcinoma. We have now examined the role of
Ck34betaE12 in discriminating between neuroendocrine and non-neuroendocrine
proliferations. METHODS AND RESULTS: We performed an
immunohistochemical study of 228 cases, comprising the whole spectrum
of lung neuroendocrine proliferations and tumours. All cases of
neuroendocrine cell hyperplasia (n = 15), tumorlet (n = 23), typical
carcinoid (n = 27) and atypical carcinoid (n = 23) were completely
negative for Ck34betaE12. Although the neuroendocrine cells of small
cell lung carcinoma and large cell neuroendocrine carcinoma were
consistently negative, a strong and diffuse positive staining was
found in the non-neuroendocrine components of combined small cell
carcinoma (three of eight cases) and combined large cell
neuroendocrine carcinoma (11 of 12 cases). In addition, scattered
Ck34betaE12+ cells were noted in 11 of 64 (17%) large cell
neuroendocrine carcinoma and in seven of 56 (12.5%) small cell
carcinoma, which were not obviously histologically combined. This
heterogeneity of high-grade neuroendocrine tumours was not observed in
carcinoids which lack Ck34betaE12 clusters of reactive cells. There
was mutual exclusion between expression of neuroendocrine markers and
that of Ck34betaE12. CONCLUSION: We conclude that 34betaE12 expression
excludes the neuroendocrine nature of tumour cells and uncovers the
real frequency of combined forms in high-grade neuroendocrine tumours.
Pulmonary
neuroendocrine carcinomas. A review of 234 cases and a statistical
analysis of 50 cases treated at one institution using a simple
clinicopathologic classification.Arch
Pathol Lab Med. 2002 May;126(5):545-53.
CONTEXT: Primary
pulmonary neuroendocrine tumors are traditionally classified into 3
major types: typical carcinoid (TC), atypical carcinoid (AC), and
large cell neuroendocrine carcinoma (LC) or small cell neuroendocrine
carcinoma (SC). Confusion arises frequently regarding the malignant
nature of TC and the morphologic differentiation between AC and LC or
SC. OBJECTIVE: To provide clinicopathologic evidence to streamline and
clarify the histomorphologic criteria for this group of tumors,
emphasizing the prognostic implications. PATIENTS: To minimize
variability in diagnostic criteria and treatment plans, we analyzed a
group of patients whose diagnosis and treatment occurred at a single
institution. We reviewed 234 cases of primary pulmonary neuroendocrine
tumors and thoroughly studied 50 cases of resected tumors from 1986 to
1995. RESULTS: On the basis of morphologic characteristics and
biologic behaviors of the tumors, we agree with many previous
investigators that these tumors are all malignant and potentially
aggressive. Based on our accumulated data, we have modified Gould
criteria and reclassified these tumors into 5 types: (1)
well-differentiated neuroendocrine carcinoma (otherwise called TC) (14
cases, with less than 1 mitosis per 10 high-power fields [HPF] with or
without minimal necrosis); (2) moderately differentiated
neuroendocrine carcinoma (otherwise called low-grade AC) (6 cases,
with less than 10 mitoses per 10 HPF and necrosis evident at high
magnification); (3) poorly differentiated neuroendocrine carcinoma
(otherwise called high-grade AC) (10 cases, with more than 10 mitoses
per 10 HPF and necrosis evident at low-power magnification); (4)
undifferentiated LC (5 cases, with more than 30 mitoses per 10 HPF and
marked necrosis); and (5) undifferentiated SC (15 cases, with more
than 30 mitoses per 10 HPF and marked necrosis). The 5-year survival
rates were 93%, 83%, 70%, 60%, and 40% for well, moderately, and
poorly differentiated, and undifferentiated large cell and small cell
neuroendocrine carcinomas, respectively. We found nodal metastasis in
28% of TC in this retrospective review, a figure higher than
previously recorded. CONCLUSION: Using a grading system and terms
comparable to those used for many years and used for neuroendocrine
tumors elsewhere in the body, we found that classification of
pulmonary neuroendocrine carcinomas as well, moderately, poorly
differentiated, or undifferentiated provides prognostic information
and avoids misleading terms and concepts. This facilitates
communication between pathologists and clinicians and thereby improves
diagnosis and management of the patient.
The surgical
spectrum of pulmonary neuroendocrine neoplasms.Chest.
2001 Jan;119(1):14-8.
OBJECTIVES: The
purpose of this study is to review our experience with the spectrum of
neuroendocrine neoplasms of the lung with emphasis on the
histopathologic classification and surgical therapy of each class of
neoplasm. DESIGN: This retrospective review covers the entire spectrum
of neuroendocrine neoplasms of the lung over an 11-year period
(January 1985 to December 1995) in a university hospital setting. Only
patients who underwent surgical resection were included in this
review. PATIENTS: During this period, a total of 77 patients underwent
lung resection for the following neuroendocrine neoplasms: typical
carcinoid (TC), 50 patients; atypical carcinoid (AC), 5 patients;
large cell neuroendocrine carcinoma (LCNEC), 9 patients; mixed
large-small cell neuroendocrine carcinoma (LSNEC), 4 patients; or
small cell neuroendocrine carcinoma (SCC), 9 patients. There were 37
men (48.1%) and 40 women (51.9%) among the patients, with a mean age
of 57.9 years (range, 14 to 87 years). INTERVENTIONS: Primary surgical
resection consisted of the following procedures: 52 lobectomies
(67.5%); 10 pneumonectomies (13%); 13 limited resections (16.9%); 1
left main bronchus sleeve resection; and 1 carinal resection. Six
patients had the following concomitant procedures: pericardiectomy, 2
patients; mediastinoscopy, 1 patient; chest wall resection, 1 patient;
stapling blebs, 1 patient; and transdiaphragmatic liver biopsy, 1
patient. Four patients underwent bilobectomies, and two patients
underwent multiple wedge resections. RESULTS: The hospital mortality
rate was 2.6% (2 of 77 patients), and both patients died of pulmonary
failure. Follow-up was obtained in 62 of 77 patients (80.9%) for an
average of 38.1 months (range, 2 to 132 months). There were a total of
13 deaths, and 8 were disease-related (LCNEC, 4 deaths; SCC, 2 deaths;
LSNEC, 1 death; and AC tumor, 1 death. The mean disease-free intervals
for patients with these neoplasms were the following: TC tumor, 41.3
months; AC tumor, 20 months; LCNEC, 20.4 months; LSNEC, 25 months; and
SCC, 48 months. The overall 3-year survival rate was 45.2% (28 of 62
patients). CONCLUSION: This report will emphasize the classification,
surgical management, and treatment considerations of pulmonary
neuroendocrine neoplasms. Despite the poor overall prognosis in
high-grade neuroendocrine tumors of the lung, surgery remains a viable
adjunct in the early stages of this disease.
Differential
distribution of the neuron-associated class III beta-tubulin in
neuroendocrine lung tumors. Arch Pathol Lab Med 2000;124:535–544.
OBJECTIVE: To
study the immunoreactivity profile of the neuron-associated class III
beta-tubulin isotype (beta III) in epithelial lung tumors. DESIGN: One
hundred four formalin-fixed, paraffin-embedded primary and metastatic
lung cancer specimens were immunostained with an anti-beta III mouse
monoclonal antibody (TuJ1) and an anti-beta III affinity-purified
rabbit antiserum. Paraffin sections from fetal, infantile, and adult
nonneoplastic lung tissues were also examined. RESULTS: In the fetal
airway epithelium, beta III staining is detected transiently in rare
Kulchitsky-like cells from lung tissues corresponding to the
pseudoglandular and canalicular but not the saccular or alveolar
stages of development. beta III is absent in healthy, hyperplastic,
metaplastic, and dysplastic airway epithelium of the adult lung. In
contrast, beta III is highly expressed in small cell lung cancer,
large cell neuroendocrine carcinoma, and in some non-small cell lung
cancers, particularly adenocarcinomas. There is no correlation between
expression of beta III and generic neuroendocrine markers, such as
chromogranin A and/or synaptophysin, in pulmonary adenocarcinomas.
Also, focal beta III staining is present in primary and metastatic
adenocarcinomas (to the lung) originating in the colon, prostate, and
ovary. beta III is expressed to a much lesser extent in atypical
carcinoids and is rarely detectable in typical carcinoids and squamous
cell carcinomas of the lung. The distribution of beta III in small
cell lung cancer and adenocarcinoma metastases to regional lymph nodes
and brain approaches 100% of tumor cells, which is substantially
greater than in the primary tumors. CONCLUSIONS: In the context of
neuroendocrine lung tumors, beta III immunoreactivity is a molecular
signature of high-grade malignant neoplasms (small cell lung cancer
and large cell neuroendocrine carcinoma) although its importance in
atypical carcinoids must be evaluated further. In addition, beta III
may be a useful diagnostic marker in distinguishing between small cell
lung cancers and certain non-small cell lung cancers (poorly
differentiated squamous cell carcinomas), especially in small biopsy
specimens. To our knowledge, beta III is the only tumor biomarker that
exhibits a substantially more widespread distribution in poorly
differentiated than in better differentiated pulmonary neuroendocrine
tumors. However, the significance of beta III phenotypes in non-small
cell lung cancer, particularly adenocarcinoma, with respect to
neuroendocrine differentiation and prognostic value, requires further
evaluation.
Carcinoid tumors
of the lung. An analysis of 65 operated cases.J
Cardiovasc Surg (Torino).
1999 Aug;40(4):607-12.
BACKGROUND: The
aim of this study was to analyse two groups of patients operated for
bronchopulmonary neuroendocrine neoplasms (bronchial carcinoid and
well-differentiated neuroendocrine carcinoma) and to investigate their
clinico-pathological data and long-term survival. METHODS: From
January 1978 to June 1996, 65 patients with bronchial carcinoids
underwent operation at our Institution. There were 33 males and 32
females, whose mean age was 49.8 years. Forty-four neoplasms (67.7%)
were considered to be central. Histology revealed 54 typical bronchial
carcinoids (83%) and 11 well-differentiated neuroendocrine carcinomas
(17%). Surgical resection of tumor and complete lymph node dissection
was performed in all cases. RESULTS: All patients entered follow-up:
5-year survival was 91% for patients with bronchial carcinoid and 49%
for those with well-differentiated neuroendocrine carcinoma (p<0.05).
Univariate analysis found that there was a significant decrease in
survival also for peripheral location of the tumor, advanced
pathologic stage and histologically positive lymph nodes. CONCLUSIONS:
These results point out that carcinoid tumors are malignant neoplasms,
so they require a complete and radical surgical resection. Most tumors
are only locally invasive and show a low aggressive behaviour;
therefore, when possible, it is recommended to attempt a limited
resection. Frozen sections of bronchial margins and complete
lymphadenectomy should be routinely performed. The same criteria
should apply to well differentiated neuroendocrine carcinomas, though
their behaviour is more aggressive.
Typical and atypical
carcinoid tumors of the lung are characterized by 11q deletions as
detected by comparative genomic hybridization. Am J Pathol
1998;153:1089–1098.
Neuroendocrine
tumors of the lung represent a wide spectrum of phenotypically
distinct entities with different biological characteristics such as
typical carcinoid tumor (TC), atypical carcinoid tumor (AC),
large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung
carcinoma (SCLC). The histogenetic relationships between TC, AC, LCNEC,
and SCLC are still unclear. This study was carried out to provide
cytogenetic data about pulmonary neuroendocrine tumors and to evaluate
their characteristic alterations and histogenetic relations for an
improved understanding of the mechanisms of tumor development.
Twenty-nine paraffin-embedded tumor samples of TC (n = 17), AC (n =
6), LCNEC (n = 3), and SCLC (n = 3) were selected for isolation of
tumor DNA and subsequent comparative genomic hybridization (CGH)
analysis. To confirm the comparative genomic hybridization results for
characteristic chromosomal imbalances, selected cases were
additionally investigated by loss of heterozygosity analysis. For
statistical evaluation, we also used comparative genomic hybridization
data from 45 published SCLC cases. DNA underrepresentations of 11q
were the most frequent findings in TC (8 of 17) and AC (4 of 6),
whereas these aberrations were rare in LCNEC (1 of 3) and SCLC (0 of
3). Furthermore, AC showed DNA underrepresentation of 10q (3 of 6) and
13q (3 of 6). In contrast, SCLC and LCNEC were characterized by a
different pattern of DNA losses (3p-, 4q-, 5q-, 13q-, and 15q-) and
gains (5p+, 17p+, and +20). Statistical analysis revealed
significantly different occurrences of 11q deletions in TC/AC versus
SCLC (45 published cases of SCLC and our 3 cases; P = 0.002; Fisher's
exact test). Thus, TC and AC display frequent loss of 11q material
including the MEN1 gene locus, which represents a characteristic
genetic alteration in these tumors. Losses of 10q and 13q sequences
allow a further cytogenetic differentiation between TC and AC. These
additional changes might be responsible for the more aggressive
behavior of AC. Three cases of LCNEC, the first to be analyzed by
comparative genomic hybridization, exhibited similar complex abnormal
patterns (4q-, 5q-, 10q-, 13q-, 15q-) to those of SCLC. Although
neuroendocrine tumors of the lung share common phenotypic features,
suggesting a genotypic relationship, they differ remarkably in their
cytogenetic characteristics, highlighting an early fundamental
molecular divergence during the development of these tumors.
Analysis of p53, K-ras,
and c-raf-1 in pulmonary neuroendocrine tumors: correlation with
histological subtype and clinical outcome. Am J Pathol
1996;148:1531–1541.
Neuroendocrine
tumors of lung, including typical carcinoid (TC), atypical carcinoid
(AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung
carcinoma (SCLC) constitute a spectrum of malignancies in which the
pathologist at times has difficulty in discerning tumor subtype and
aggressiveness in a reproducible fashion. Therefore, 59 primary
neuroendocrine lung tumors including 10 TCs, 26 ACs, 15 LCNECs, and 8
SCLCs were selected from cases collected from 1976 to 1988 and
immunostained for p53 protein. All of these tumors were also genotyped
for specific point mutational damage affecting p53 (exons 5, 7, and 8;
with ACs additionally sequenced for p53 exon 6); 13 tumors for K-ras-2
(exon 1); and 31 tumors for c-raf-1 (exon 15) growth-regulatory genes.
Genotyping was performed on topographically selected, minute tumor
samples removed from unstained formalin-fixed, paraffin-embedded
tissue sections (topographic genotyping) using polymerase chain
reaction and direct sequencing. The distribution of p53
immunohistochemical staining had four patterns: negative in TCs,
one-half of ACs, 3 of 15 LCNECs, and 1 of 8 SCLCs; less than 10% but
more than five tumor cells per 10 high power fields (focal) in a
subset (7 of 26) of aggressive ACs; 10 to 49% of tumor cells (patchy)
in a subset (6 of 26) of ACs with a higher grade of aggressiveness;
and 50 to 100% of tumor cells (diffuse), exclusively seen in LCNECs
(12 of 15) and SCLCs (7 of 8). Three patterns of immunohistochemical
staining intensity of p53 protein were seen: negative, weak or mild,
and moderate to marked. SCLCs and LCNECs accounted for cases of
moderate to marked staining and were the only ones to have mutations
in p53 exons 5, 7, or 8. No mutations were found in AC and TC, showing
absent to weak staining and no staining, respectively. The difference
in distribution and staining intensities between LCNEC and SCLC
compared with AC and TC was statistically significant (P < 0.001).
Patients having AC with patchy p53 immunostaining usually had survival
limited to 3 years, whereas those having AC with focal p53
immunostaining subsequently developed metastatic or recurrence of AC
disease (P < 0.05). The absence of point mutations in cases with
patchy or focal immunostaining suggests increased expression of
wild-type p53 tumor suppressor protein likely in response to growth
deregulation in a more aggressive subtype of AC. A novel hypothesis is
presented in regard to these findings. K-ras-2 and c-raf-1 gene
sequence analysis showed no evidence of point mutational change in any
of the tumors studied. The TC and AC categories are therefore
genetically distinct from the higher grade neuroendocrine SCLC and
LCNEC. Immunohistochemistry for p53 on AC lung tumors may be helpful
to delineate cases at higher risk for aggressive behavior.
Additionally, although LCNEC is categorized as a non-small-cell
carcinoma, it is more akin genetically and immunohistochemically to
SCLC.
Apoptosis-related
factors p53, Bcl-2, and Bax in neuroendocrine lung tumors. Am J Pathol
1996;149:1941–1952.
Neuroendocrine
(NE) lung tumors comprise four classes of progressive aggressiveness
for which proliferation and apoptosis rates could both contribute to
their distinctive behavior. As p53 mutations may favor escape from
apoptosis through changes in Bcl2-Bax expression balance, which are
survival and apoptotic genes, respectively, we studied 121 NE lung
tumors (16 typical carcinoids (TC), 5 atypical carcinoids (AC), 29
large-cell NE carcinomas (LCNECs), and 71 small-cell lung carcinomas (SCLCs)
using immunohistochemistry. We quantified apoptosis by terminal-deoxynucleotidyl-transferase-mediated
deoxyuridine triphosphate nick end labeling (TUNEL) in 31 of these
cases. There was a significant increase of p53 mutant immunophenotype
(defined as immunoreactivity with at least two antibodies for at least
20% of tumor cells) between atypical/typical carcinoids group and the
LCNEC/SCLC group (P = 0.0003). There was an inverse correlation (P <
0.0001) between the scores of Bax and Bcl2 expression in individual
tumors and a significant inversion of the Bcl2. Bax ratio between
low-grade (typical and atypical carcinoids) and high-grade (LCNECs and
SCLCs) tumors with a predominant Bax expression in the first group and
predominant Bcl2 expression in the second. Whereas carcinoids had
variable apoptotic indexes, LCNECs had high indexes (1.3 to 6.8%),
Bcl2 overexpression, Bax down-regulation, and Bcl2.Bax ratio > 1
correlated with lower apoptotic index in both LCNEC and the pool of
LCNECs and SCLCs (P < 0.05) and a lower survival rate in the group of
atypical and typical carcinoids and LCNECs (P < 0.002). The highest
levels of Bcl2 expression and Bcl2.Bax ratios were associated with p53
mutant immunophenotype (P = 0.02). Our results suggest that
aggressiveness in NE lung tumors could be linked, in addition to
proliferation, to apoptosis-related factors.
Differential
diagnostic patterns of lung neuroendocrine tumours. A clinico-pathological
and immunohistochemical study of 122 cases.Virchows
Arch A Pathol Anat Histopathol.
1992;420(3):201-11.
A series of 3
tumourlets (TLs), 81 typical carcinoids (TCs), 14 atypical carcinoids
(ACs) (well-differentiated neuroendocrine carcinomas, WDNCs) and 24
small cell-intermediate cell carcinomas (SCC-ICCs) of the lung were
studied. Histopathological features were correlated with amine and
peptide hormone immunoreactivity and with clinical data. All types of
tumours expressed general neuroendocrine (NE) markers: Grimelius
positivity and chromogranins were detected more frequently in
well-differentiated (TLs, TCs) than in less well differentiated
tumours [ACs (WDNCs) and SCC-ICCs] whereas neuron specific enolase (NSE)
was prominent in the latter tumours. TLs and peripheral TCs were
benign, often showing a paraganglioid pattern and frequently
expressing gastrin-releasing peptide (GRP), which is present in the
peripheral airways of normal lung. Central TCs were associated with
lymph node metastases in 8.5% of the cases, frequently had a
trabecular architecture, often associated with human milk fat globule
2 (HMFG2)-positive acinar and rosette-like structures, and were mainly
immunostained for the alpha-subunit of human chorionic gonadotrophin
(alpha-hCG) and serotonin. ACs (WDNCs) were associated with
intrathoracic and/or extrathoracic metastases in 57.1% of the cases
with a mortality rate of 35.7%. Their histological and cytological
features were intermediate between those of TCs and SCC-ICCs. ACs (WDNCs)
expressed serotonin and alpha-hCG less frequently than TCs. All
SCC-ICCs were surgically treated and displayed a mortality rate of
91.6% with a mean survival of 10.2 months after operation. These
tumours were characterized by high expression of HMFG2 and NSE, while
the expression of both orthotopic (serotonin, GRP) and ectopic (ACTH)
specific NE substances was very low. Since all TCs (either central or
peripheral) had a favourable outcome, while about 36% of ACs (WDNCs)
were fatal, the latter seem more appropriately designated
"well-differentiated NE carcinomas". The differential diagnosis
between different NE tumours of the lung is important and is mainly
based on morphology. Both panendocrine and specific
immunohistochemical markers are helpful in distinguishing the less
aggressive, mostly benign varieties from the more malignant varieties.
Bronchial carcinoid
tumors: a retrospective analysis of 126 patients. Ann Thorac Surg
1992;54:50–55.
From 1970 until
1990, 8,958 cases of primary carcinoma of the lung were diagnosed at
the Duke University Medical Center. During the same period, 126
patients (mean age, 53 +/- 13 years) were diagnosed with bronchial
carcinoid. The overall survival was 78% for 5 years and 71% for 10
years. Surgical treatment in 106 patients included pneumonectomy (15),
lobectomy (63 with 9 bronchoplastic procedures), stapled wedge
resection (22), and bronchoscopic laser resection (6). The method of
diagnosis was chest roentgenography (121), chest computed tomography
(77), mediastinal tomography (31), bronchoscopy (81), bronchoscopic
brushing and washing (50), bronchoscopic biopsy (40), transthoracic
needle biopsy (27), thoracotomy (100), and autopsy (5). Univariate
analysis of the medical history, presenting signs and symptoms,
diagnostic test results, and pathologic data predicted improved
survival (p less than 0.001) for: female sex (n = 58), asymptomatic
presentation (n = 47), normal serum serotonin or urinary
hydroxyindoleacetic acid levels (n = 76), peripheral location of the
primary tumor (n = 50), pathologic stage I or II (n = 91), negative
lymph nodes (n = 80), primary tumor 2 cm or less in diameter (n = 67),
and typical histology (n = 80). No significance (p greater than 0.1)
was observed for age, smoking history, race, family history of
carcinoid, environmental exposure, or hemoptysis. The most important
factors affecting survival defined by multivariate analysis were (p
less than 0.01) pathologic stage, atypical histology, and asymptomatic
presentation. Bronchial carcinoid tumors are unique, making up 1% to
2% of primary lung neoplasms and having an excellent prognosis after
resection with a 95% 5-year and 93% 10-year survival for pathologic
stage I disease.
Neuroendocrine
neoplasms of the lung. A clinicopathologic update.J
Thorac Cardiovasc Surg. 1989
Sep;98(3):321-32.
One hundred
forty-six cases of pulmonary neuroendocrine tumors are assessed
according to the classification of Gould and associates and are
evaluated for their clinical presentation and subsequent clinical
course. Bronchial carcinoids are characteristically found to be
central tumors often occurring in comparatively young patients;
surgical resection with minimal but clear margins is usually curative.
The long-term prognosis is excellent in the majority of patients,
although rarely regional nodal and distant metastases develop.
Well-differentiated neuroendocrine carcinomas are most frequently
peripheral tumors. In stage I and II disease, surgical resection alone
is curative and patients with locally advanced tumors may have a
prolonged disease-free interval. The overall prognosis is less
favorable than that of bronchial carcinoids but considerably better
than that of small cell neuroendocrine carcinomas, with which they are
still at times confused. Intermediate-sized cell neuroendocrine
carcinomas are often wrongly categorized as large cell
undifferentiated carcinoma. They have a distinctly aggressive clinical
course comparable with that of small cell neuroendocrine carcinoma and
should be treated similarly. Small cell neuroendocrine carcinomas are
aggressive, rapidly disseminating neoplasms. Even in clinical stage I
tumors, patients must be considered to have disseminated metastases.
The role of surgical therapy in these two latter tumor types is
adjuvant to aggressive systemic chemotherapy.
Neuroendocrine
neoplasms of the bronchopulmonary tract. A classification of the
spectrum of carcinoid to small cell carcinoma and intervening
variants.J
Thorac Cardiovasc Surg. 1985
Jun;89(6):819-25.
Eighty-one
primary pulmonary neuroendocrine neoplasms were assessed by the
classification of Gould and associates. The neuroendocrine features of
these tumors were studied by a combination of conventional light
microscopy, electron microscopy, and immunohistochemical staining for
hormonal substances and neuron-specific enolase. In each case,
clinical follow-up was obtained to test the prognostic value of this
new pathological classification. This study indicated that bronchial
carcinoids are very low-grade neuroendocrine neoplasms that are
locally invasive and only occasionally metastasize late in their
course. Well-differentiated neuroendocrine carcinomas are relatively
low-grade carcinomas that either present with or subsequently develop
nodal or distant metastases in 73% of patients. Intermediate cell
neuroendocrine carcinomas are highly aggressive tumors often
mistakenly called "large cell undifferentiated carcinoma." Their
clinical course is comparable to that of small cell neuroendocrine
carcinomas, which has a mean survival of 9 months. The different
clinical courses of these tumors demonstrate the predictive value of
the proposed classification. It appears particularly valuable to
identify well-differentiated neuroendocrine carcinoma as a low-grade
carcinoma, distinct from true bronchial carcinoids. This
classification may resolve some discrepancies regarding the therapy
for and prognosis of "carcinoids" and their presumed variants.
Carcinomas of the
lung with neuroendocrine differentiation.Semin
Diagn Pathol. 1985 Nov;2(4):235-54.
While there
are examples of each of the histologic types of bronchogenic carcinoma
in which ectopic hormone production has been demonstrated, three
groups of lung cancers manifest this type of differentiation with
great regularity. These are the carcinoid, atypical carcinoid, and the
small cell carcinoma, which have been called neuroendocrine carcinomas
of the lung. The carcinoids are neoplasms with a heterogeneous array
of histologic appearances that share relatively uniform nuclear
features, the absence of both tumor necrosis and mitotic figures, and
a good prognosis. Neuroendocrine differentiation is demonstrable with
such regularity in carcinoids that the diagnosis is not considered
tenable in the absence of at least one of the following features:
argyrophilia, the demonstration of neuron-specific-enolase or
neuropeptides by immunohistochemistry or other techniques, or the
demonstration of numerous dense-core membrane-bound granules, usually
150 to 250 nm in diameter, by electron microscopy. The atypical
carcinoids (well or moderately differentiated neuroendocrine
carcinomas) share the neuroendocrine differentiation of the carcinoids
and many of their histologic features, but are distinguished by the
presence of tumor necrosis, more anaplastic large cell nuclei with
numerous mitotic figures, and a distinctly worse prognosis. They are a
heterogeneous lot with some similarities to carcinoids, small cell
carcinomas, and large cell or adenocarcinomas. The demonstration of at
least one of the neuroendocrine features listed above is considered
necessary for this diagnosis. Small cell carcinoma is also a
heterogeneous group of neoplasma primarily distinguished by their
finely granular chromatin pattern which correlates with a much worse
prognosis but a higher likelihood of response to chemotherapy and
radiotherapy. Many small cell carcinomas share the neuroendocrine
differentiation of the carcinoids or atypical carcinoids, but some do
not and the demonstration of these features is not a requisite for
inclusion in the small group. The morphologic demonstration of
neuroendocrine differentiation may be more difficult in small cell
carcinomas, but they more frequently produce clinically important
amounts of ectopic neuropeptides. While the term neuroendocrine
carcinoma of the lung includes several quite different entities and
does not by itself convey histogenetic or prognostic implications, the
demonstration of neuroendocrine differentiation in pulmonary neoplasms
is an important procedure when combined with the recognition of other
cytologic and histologic features.
Immunohistochemical and ultrastructural analysis of bronchopulmonary
neuroendocrine neoplasms. II. Well-differentiated neuroendocrine
carcinomas.Ultrastruct
Pathol. 1984;7(2-3):185-99.
We have attempted
to characterize a group of bronchopulmonary neoplasms that share
certain structural features with true carcinoids but appear distinctly
more pleomorphic and behave far more aggressively. In reviewing our
files from 1973 to 1982, 11 such neoplasms were identified; the
original diagnoses were "atypical bronchial carcinoid" (3 cases),
"malignant carcinoid" (1 case), "bronchial carcinoid" (3 cases),
"peripheral carcinoid" (2 cases), and "peripheral oat cell carcinoma"
(2 cases). Of the 11 neoplasms, 5 were central and 6 were peripherally
located. At presentation, 7 patients had lymph node metastases and 1
had a distant metastasis. No patient had a conventionally defined
hormonal syndrome; however, 2 patients had a history of episodic
flushing, one of which was associated with diarrhea. All cases were
studied by light microscopy and light microscopic immunohistochemistry
for NSE (neuron-specific enolase), serotonin, and broad-spectrum
neuropeptides. Five cases were studied by electron microscopy. By
light microscopy, the tumors were composed of solid clusters of
polygonal to fusiform cells in an evident organoid arrangement. Foci
of glandular and/or squamous differentiation were seen in 7 cases.
Pleomorphism was moderate and mitoses were readily found. Focal
necrosis was seen. By immunohistochemistry, 10 cases expressed NSE
immunoreactivity. All cases demonstrated hormonal immunoreactivity; in
9 cases, immunoreactivity for more than one hormone was observed. The
hormones most frequently expressed were serotonin, bombesin, gastrin,
leu-enkephalin, and ACTH. By electron microscopy, all cases studied
contained heterogeneous populations of neurosecretory granules; the
latter, however, were not abundant and tended to aggregate either in
the basal pole of the cells or, more frequently, interlacing "dendritelike"
cytoplasmic processes. Aggregates of intermediate filaments were
frequently seen. Basal lamina deposition was seen but gaps and larger
areas of discontinuity were frequent. We believe that these neoplasms
constitute a distinct pathologic entity for which the term
"well-differentiated neuroendocrine carcinoma" has been proposed.
Clinically, these tumors merit special attention since they are
demonstrably more aggressive than true carcinoids but are distinctly
less malignant than the intermediate or small cell variants of
neuroendocrine carcinoma.
Amine and peptide hormone production by lung
carcinoid: a clinicopathological and immunocytochemical study.J
Clin Pathol. 1984 Aug;37(8):931-6.
A consecutive series of 38
lung carcinoid tumours (36 surgical and two necropsy specimens) was
studied. Histopathological features and amine and peptide hormone
immunoreactivity were correlated with gross characteristics (size,
location) and clinical data. Peripheral carcinoids were detected a
decade later than central carcinoids and tended to be bigger. In
general, the histological characteristics of peripheral and central
carcinoids were similar; atypical features, however, were more common
in peripheral carcinoids. Most carcinoids contained many argyrophilic
cells (58%). Although argentaffinic cells were not found, serotonin
immunoreactive cells were present in 32% of the tumours. Peptide
hormone immunoreactivity (adrenocorticotrophic hormone (ACTH),
calcitonin, somatostatin, gastrin) was rare. In one case massive ACTH
production had caused clinically manifest Cushing's syndrome. In two
other cases few ACTH immunoreactive cells were found and in one case
calcitonin immunoreactive cells were present. The relative rarity of
hormone production in lung carcinoids and the predominantly benign
course of the tumour preclude the use of peptide hormone production as
a prognostic indicator.
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