|
Immunohistochemical evaluation of neuroendocrine cells and neoplasms
of the lung.Pathol
Res Pract. 1988 Apr;183(2):200-13.
The dispersed
neuroendocrine (NE) system is represented in the bronchopulmonary
tract by submucosal nerves and ganglion cells and, in the mucosal
lining by solitary NE cells and neuroepithalial bodies (NEB's). The
latter two components variably express pan-NE markers including NSE,
chromogranin (s) and, notably, synaptophysin. The expression of
serotonin, bombesin, calcitonin and leu-enkephalin has been well
established; additional eutopic materials include somatostatin and
calcitonin gene-related peptide. Solitary NE cells and NEB's are
epithelial structures as defined by their consistent cytokeratin
expression. Hyperplasia and dysplasia of NE cells may be found in
association with various forms of chronic injury; they have been noted
in chronic bronchiectasis and in the vicinity of neoplasms of various
types. Hyperplastic and dysplastic pulmonary NE cells frequently
express ectopic materials particularly ACTH. NE neoplasms of the
bronchopulmonary tract comprice a spectrum that includes a) carcinoids,
b) well differentiated NE carcinomas, c) intermediate cell NE
carcinomas and d) small cell NE carcinomas. The precise pathologic
criteria defining these entities are discussed in detail as are their
clinical implications. The entire spectrum of lung NE neoplasms
express NE markers demonstrable by immunocytochemistry; these include
pan-NE markers, serotonin and numerous neuropeptides. The expression
of multiple hormonal materials is frequent. Within any given tumor,
some variation in expression may be noted in different sites and in
different periods of the "normal" or therapeutically modified lifespan
of the tumor. The entire spectrum of lung NE neoplasms is epithelial
for they express cytokeratin polypeptides and desmoplakin; subsets of
the tumors coexpress cytokeratins and neurofilament proteins. Also,
subsets of these NE neoplasms may be immunostained with monoclonal
antibodies to antigens related to exocrine phenotype suggesting focal
amphicrine features.
Synaptophysin expressed in the bronchopulmonary tract: neuroendocrine
cells, neuroepithelial bodies, and neuroendocrine neoplasms.
Differentiation. 1987;34(2):115-25.
Synaptophysin is
an integral membrane glycoprotein with an Mr of 38,000 that occurs in
the small, clear vesicles present in neuronal cells and tumors as well
as in pancreatic islet cells and various neuroendocrine (NE)
carcinomas. We found that synaptophysin is also expressed in normal NE
cells of the lungs of newborn rabbits and mice as well as of human
fetuses. In bronchial ganglion cells and in nerves, synaptophysin is
coexpressed with neurofilament proteins (NFPs), whereas in solitary NE
cells and in at least some of the neuroepithelial bodies (NEBs) of the
bronchial mucosal lining, synaptophysin coexists with cytokeratins. We
also studied a series of NE neoplasms of the lung covering the entire
spectrum of differentiation (i.e., from carcinoids to small-cell NE
carcinomas), and found that synpatophysin was present in the majority
of them. In these tumors, synaptophysin was invariably coexpressed
with cytokeratin filaments and desmoplakin, as well as, occasionally,
with NFP. Synaptophysin was identified throughout, the whole range of
these NE neoplasms, i.e., from benign to low-grade to aggressive and
rapidly metastasizing carcinomas; its presence was unaffected by the
highly variable expression of serotonin and/or neuropeptides in these
neoplasms, and was unrelated to the presence or absence of associated
endocrine syndromes. Our findings indicate that synaptophysin occurs
in the neural as well as in the epithelial components of the dispered
NE system of the lung as well as in the majority of NE neoplasms of
this organ, and that the expression of this protein is therefore
independent of the cytoskeletal characteristics and other
differentiation features of both normal and transformed NE cells of
the lung. We emphasize the value of synaptophysin as an
immunocytochemical marker of NE differentiation.
Neuroendocrine cells in the developing human lung:
morphologic and functional considerations.Pediatr
Pulmonol. 1985 May-Jun;1(3 Suppl):S21-9.
The structure,
distribution, and frequency of neuroendocrine (NE) cells in human
fetal lung from early stages of development to term are described.
Neuroendocrine cells were studied by electron microscopy and
immunostaining for serotonin and bombesin, recently identified markers
of these cells in human lung. The differentiation of NE cells within
the airway epithelium proceeded centrifugally and followed the
development of the bronchial tree. The first NE cells, identified at 8
weeks' gestation, appeared well-differentiated compared with adjacent
epithelial cells, and were immunoreactive for serotonin. The first
bombesin-immunoreactive cells were detected at 10 weeks' gestation.
Fetal lungs from midgestation contained several ultrastructurally
distinct NE cell types, distributed singly and in groups. Serotonin-immunoreactive
cells were more frequent during early stages of development and were
predominantly located in larger airways. Bombesin-immunoreactive cells
became more numerous towards term and were concentrated in small
peripheral airways. The well-differentiated appearance and large
number of NE cells in fetal lung, and their increase in number towards
term, suggest an important role for these cells during intrauterine
life and neonatal adaptation. Whether this role involves neurohormonal
regulation of fetal-neonatal pulmonary circulation or local (paracrine)
or endocrine function requires further investigation.
Neuroendocrinelike (small granule) epithelial cells of
the lung.Environ
Health Perspect. 1984 Apr;55:271-95.
The presence of
neuroendocrinelike epithelial cells in the lung of numerous species
has been demonstrated by light and electron microscopy. Histochemical
methods used to identify these cells have included staining with
silver, amine-type fluorescence (APUD cell), periodic acid Schiff
(PAS)-lead hematoxylin, and immunohistochemical localization of
neuron-specific enolase. Cytoplasmic dense core vesicles (70-200 nm in
diameter) have served as the major ultrastructural characteristic.
Lung neuroendocrinelike cells have been shown to occur in fetal and
adult mammals as solitary-type cells or as distinct organoids known as
neuroepithelial bodies ( NEBs ). Although the frequency of both
populations is considered low, solitary-type cells with dense-core
granules can be found in as high as 5% of epithelial cells in the
cricoid region of the guinea-pig larynx. The solitary cells can be
found throughout the airways of mammals, whereas the NEBs are confined
to the intrapulmonary airways. Unmyelinated fibers have been traced
from the lamina propria and into the NEB, where they ramified between
the component cells of the NEB. The function of lung
neuroendocrinelike cells is not known, but morphological and
cytochemical studies suggest that the NEBs are intrapulmonary
chemoreceptors that can respond to changes in airway gas composition.
Hypoxia or hypercapnia has been shown to decrease the amine
cytofluorescence in these organoids and apparently to increase the
exocytosis of dense core vesicles from the basal region of the cell.
Immunohistochemical studies have suggested that some lung epithelial
cells may contain a known neuropeptide(s), but further investigation
is needed to confirm the presence of such compounds in lung
neuroendocrinelike cells and their physiochemical properties. Apparent
hyperplasia of lung neuroendocrinelike cells can occur readily in
hamsters treated with diethylnitrosamine. It has been postulated that
human lung tumors with endocrinelike properties, namely, bronchial
carcinoids and lung small cell carcinomas, may originate from lung
neuroendocrinelike cells. However, a more plausible explanation, based
on cytokinetic studies of epithelial neuroendocrinelike cells in the
lung and other organs, is that these cells originate from a
nonneuroendocrine population. Interaction of such a progenitor cell
population with selected carcinogens may lead to stimulation of the
rate of normal differentiation or, alternately, to selection of an
abnormal route.
Neuroendocrine
components of the bronchopulmonary tract: hyperplasia, dysplasias, and
neoplasms. Lab Invest 1983;49:519–537
The dispersed neuroendocrine (NE) system is represented in the
bronchopulmonary tract by the solitary neuroendocrine cells and the
neuroepithelial bodies (NEBs). Immunohistochemically, neuron-specific
enolase, serotonin, bombesin, and calcitonin are demonstrable in both
components, whereas leu-enkephalin is demonstrable only in solitary NE
cells. The precise function of and interplay between these two
components under physiologic and pathologic conditions are not
entirely clear. Current indications are that NEBs act as
intrapulmonary chemoreceptors sensitive to hypoxia and hypercapnia,
whereas solitary NE cells may have a paracrine, regulatory function.
Even less clear is the possible role of solitary NE cells and NEBs in
the processes associated with intrauterine and neonatal pulmonary
growth and maturation. Various experimental manipulations have
resulted in proliferation of solitary NE cells and NEBs. Of particular
interest is the apparently selective proliferative effect on NEBs
shown by several nitroso compounds. Diethylnitrosamine administration
to hamsters for several weeks results in an increase in the number of
NEBs and an increase in the number of cells per NEB. These
hyperplastic NEBs express the same immunoreactive hormones as their
normal counterparts. However, when NEB cells from diethylnitrosamine-treated
hamsters are cultured in vitro a notable proportion of the resulting
endocrine cells express ACTH immunoreactivity. Interestingly, the
neoplasms that eventually develop in these hamsters are not comprised
of NE cells. Studies on human bronchi from specimens resected for
various types of neoplasms and for bronchiectasis with and without
associated chronic obstructive pulmonary disease have revealed
frequent hyperplasias of solitary NE cells and NEBs. In about 10% of
the specimens, dysplastic aggregates of solitary NE cells and NEBs are
found. Unexpected "microcarcinoids" and tumorlets are also seen. The
mildly and moderately hyperplastic solitary NE cells and NEBs tend to
express the hormones indigenous to the bronchi, whereas in the
severely hyperplastic and dysplastic cells, "ectopic" hormones may
also be expressed; the latter include predominantly ACTH and
vasoactive intestinal polypeptide. A distinct hyperplasia of NEBs has
been found in the lungs from individuals living at altitudes ranging
from 3400 to 4300 meters; these changes may represent an adaptive
response to chronic hypoxia parallel to the hyperplastic carotid
paraganglia that may be found in the same type of population.
Bronchopulmonary NE neoplasms comprise a spectrum that includes
typical carcinoids, well-differentiated NE carcinomas, and NE
carcinomas of intermediate and small cell types. Typical carcinoids
are predominantly central, display little if any pleomorphism, are
richly granulated by electron microscopy, and by immunohistochemistry
express predominantly, although not exclusively, hormones indigenous
to their site of origin.
Neuroendocrine cells
of the lung. An overview of morphologic characteristics and
development.Exp
Lung Res. 1982 Nov;3(3-4):185-208.
The detailed
morphology of pulmonary neuroendocrine (NE) cells has been defined
only during the last decade. The purpose of this paper is to review
the main morphologic features of the NE cells, to review the methods
and techniques used for their identification, and to discuss the
development and functional significance of these cells. The main
emphasis is on NE cells in human lung, but where appropriate, studies
in animal lungs are also included. NE cells are present in the airway
epithelium of human and various animal species and occur singly as
well as in clusters called neuroepithelial bodies (NEB). The general
cytochemical features (common to both single NE cells and NEB) include
cytoplasmic argyrophilia, fluorogenic amine content, positive staining
with lead-hematoxylin, and masked metachromasia. These staining
properties are similar to those found in APUD cells scattered in
various tissues. More specific cell markers are immunoreactivity to
peptide hormones (bombesin, calcitonin, leu-enkephalin) identified so
far in NE cells of human lung, and immunoreactivity to serotonin found
in both human and animal lungs. At the ultrastructural level, NE cells
are characterized by the presence of cytoplasmic dense core granules
(90-150 nm in diameter), which are considered the storage site of
amine and peptide hormones. The distinctive feature of NEB, not found
with single NE cells, is the presence of nonmyelinated nerve endings
in contact with granulated cells, and positive staining for
acetylcholinesterase. The single NE cells are scattered throughout the
tracheobronchial epithelium, whereas NEB are found only within the
intrapulmonary airways. In postnatal lungs, both the single NE cells
and NEB appear concentrated in small peripheral airways. In developing
human lung, the first NE cells appear at 8 weeks' gestation, when all
other epithelial cells are still undifferentiated. The development and
cytodifferentiation of NE cells progresses in a centrifugal direction.
By the end of the glandular period, single and groups of NE cells are
found along the entire length of primitive bronchial epithelium. Based
on differences in the size and morphology of cytoplasmic granules,
three distinct types of NE cells can be recognized. During terminal
stages of development, NE cells appear in small peripheral airways and
primitive saccules. The functional considerations include the possible
role of NE cells as endocrine, paracrine, or receptosecretory cells
involved in neurohormonal regulation of pulmonary vascular or
bronchial responses, and possible function of NEB as intrapulmonary
hypoxia-sensitive chemoreceptors.
|
