So-called "minute pulmonary chemodectoma": a tumor not related to paragangliomas.

Twenty-six cases of so-called "minute pulmonary chemodectoma" are presented. The patient population showed a marked female preponderance, and there appeared to be an association of the lesion with pulmonary injury from a variety of causes including cardiac failure, chronic bronchitis and emphysema, and thromboemboli. Half the cases had multiple tumors. Microscopically, the tumors consisted of nests of cells in the interstitial tissue near small veins. Argentaffin and argyrophil stains failed to demonstrate cytoplasmic granules in any case. By electron microscopy, the nests were composed of large cells with broadly interdigitating processes connected by many well-formed desmosomes. The cytoplasm was filled with numerous 60-A filaments. The Golgi apparatus was prominent, while other organelles were sparse. No secretory granules were identified. It is concluded that the fine structure and lack of silver-positive granules are inconsistent with the morphology of previously reported paragangliomas, but that there is a resemblance at the light and electron microscopic level to meningeal arachnoed cells and the cells of meningiomas.     

Carcinoid tumors of the thymus. An immunohistochemical study

Five carcinoid tumors of the thymus were screened immunohistochemically for the occurrence of neuropeptides (ACTH, calcitonin, calcitonin gene-related peptide, cholecystokinin, gastrin, neurotensin, somatostatin, substance P), as well as of serotonin, chromogranin A, and neuron-specific enolase. Most of the patients exhibited local symptoms evoked by growing tumor masses in the upper mediastinum without any clinical evidence of endocrine activity. Light and electron microscopic examination showed characteristic uniform large epithelial cells in polar or palisade arrangement, containing variable amounts of electron-dense secretory granules. Only a few of the tested neuropeptide antisera reacted with the investigated tumors. Cholecystokinin-immunoreactive cell populations were seen in all tumors. Expression of neurotensin could be observed in three neoplasms, two of which also exhibited ACTH immunoreactivity. Chromogranin A-immunoreactive cells were found in two neoplasms. Neuron-specific enolase showed strong staining in three tumors, one of the tumors also being immunoreactive for calcitonin. The results were confirmed by control reactions. Apart from the demonstration that conventional marker proteins are not reliable in identifying all carcinoid tumors, the present study proves that the visualization of neuropeptide-immunoreactive cells in thymus carcinoids does not necessarily correspond to the manifestation of the clinical symptoms. Furthermore, each of the investigated neoplasms, as also known from other carcinoid tumors, appears to be able to produce more than one hormone.     

Aortico-pulmonary paraganglioma: report of a case with ultrastructural study and review of the literature.

The light microscopic and ultrastructural features of an aortico-pulmonary paraganglioma (A-PP) are presented. The tumor was characterized by organoid clustering of neoplastic chief cells to form Zellballen. Argyrophilic granules were demonstrated within chief cell cytoplasm using a modified Grimelus technique. Ultrastructurally, three distinct cell types were present within the tumor: endothelial cells, pericytes and neoplastic chief cells. Membrane-bound neurosecretory granules were present and measured 100 to 2000 nm in diameter. "Light" and "dark" chief cells were less distinct than previously reported in other head and neck paragangliomas. Analysis of the 36 documented A-PP reported in the English literature reveals that the tumor has been either incompletely excised or has been considered unresectable in one-third of the cases. The reported surgical mortality is 9%, or approximately equal to the incidence of malignant behavior. The treatment of choice is surgical resection but when this is not possible, radiation may be a useful adjunct in therapy.     

A retroperitoneal endocrine carcinoma

A case of endocrine carcinoma in the retroperitoneal cavity of a 41-year-old woman is reported. Tumor cells were negative for argentaffin and positive for argyrophil reactions. Immunohistochemically, vasoactive intestinal polypeptide, hCG-alpha, and somatostatin were identified. Electron microscopically, numerous secretory granules measuring 210 to 280 nm in diameter and with distinct limiting membranes were seen in the tumor cells. Discussion was focused on the origin of endocrine tumor cells in the retroperitoneal cavity.     

Two cases of paragangliomas of the cauda equina--case reports and review of the literature

Paragangliomas are tumors arising in the paraganglia and rarely occurring in the cauda equina. We report two cases of paraganglioma arising in this region. The tumors exhibited a typical "Zellballen" pattern, and immunohistochemical studies were positive for neuron-specific enolase, but negative for S-100 protein and glial fibrillary acidic protein. Electron microscopic studies confirmed electron-dense neurosecretory types of granules in the tumor cells. Only 23 cases of paragangliomas in this region have been previously reported. A brief review of the literature is included.     

Neurohormonal peptides in ovarian carcinoids: an immunohistochemical study of 81 primary carcinoids and of intraovarian metastases from six mid-gut carcinoids

Eighty-one primary ovarian carcinoids and intraovarian metastases from six mid-gut carcinoids were examined for the presence of tumor cells immunoreactive with antisera raised against various neurohormonal peptides, mostly of gastroenteropancreatic (GEP) origin. Twenty of the primary and two of the metastatic carcinoids contained such tumor cells. The incidence of tumors with any kind of neurohormonal peptide immunoreactive tumor cells was 53% in the trabecular carcinoids, and 42% in the strumal carcinoids, whereas the incidence was much lower (7%) in the insular type. Immunoreactive pancreatic polypeptide (PP), glucagon, enkephalin, and somatostatin were those neurohormonal peptides most commonly observed in the tumor cells of the primary carcinoids. Those less commonly found were substance P, calcitonin, VIP, neurotensin, beta-endorphin, and ACTH. Four metastatic carcinoids were nonreactive with all the antisera used. Cells storing immunoreactive insulin, glucagon, PP, VIP, gastrin, substance P, or enkephalin were found in one of the two remaining metastatic carcinoids; in the other only gastrin-immunoreactive tumor cells were observed. The occurrence and distribution of tumor cells storing the neurohormonal peptides in ovarian carcinoids are discussed in relation to their possible origin in the ovary and to carcinoids in the gut.     

Multihormonal carcinoid tumor of the pancreas. Secreting growth hormone-releasing factor as a cause of acromegaly

This report describes the histologic, immunocytochemical, and ultrastructural study of a multihormonal carcinoid tumor of the pancreas, secreting a growth hormone releasing factor (GRF) which provoked acromegaly. The patient presented a nonfamilial multiple endocrine neoplasia, type 1. The absence of radiologic signs of a pituitary adenoma in conjunction with elevated plasma levels of pancreatic polypeptide, glucagon, somatostatin, as well as growth hormone (GH), led to the discovery of the tumor. Its surgical excision produced a rapid disappearance of most of the clinical and biologic disorders. No immunoreactive GH was found in the tumor using radioimmunoassay and immunocytochemistry. In contrast, three peptides with GH-releasing activity were extracted and characterized. Immunocytochemistry showed that the GRF-reactive cells, together with rare somatostatin-storing cells, made up areas which demonstrated a medullary pattern of growth with extracellular amyloid deposits. Under electron microscopic examination, actively secreting cells were observed which carried endocrine granules of 100 to 150 nm in diameter. The other regions of the tumor presented a different type of growth and were composed of pancreatic polypeptide-, glucagon-, or somatostatin-reacting cells. Cells immunostained with antisera raised against beta-endorphin were also noted. These data suggest that GRF may be a new biologic marker for pancreatic endocrine tumors.     

Neuroendocrine (Merkel cell) skin cancer. Electron microscopic study

The study is concerned with the results of light and electron microscopic examination of 2 cases of neuroendocrine (Merkel cell) carcinoma of the skin. Both patients developed multiple widely-distributed intra- and subcutaneous nodules. Histologically, tumors were mostly trabecular. Electron microscopic examination revealed neuroendocrine secretory granules, small bundles of intermediate fibers, a well-defined Golgi complex and a relatively high level of vesicular structures. There were some basal membrane fragments. It is suggested that they originate from polypotential epithelial stem cells.     

The absence of autonomic perivascular nerves in human colorectal liver metastases.

The peptidergic/aminergic innervation of normal liver and tumour blood vessels was investigated in order to determine vascular control with a view to improving the efficacy of hepatic arterial cytotoxic infusion in the treatment of colorectal liver metastases. Selected areas of liver metastases and macroscopically normal liver from resection specimens (n = 13) were studied using light microscope immunohistochemistry for the presence of protein gene product 9.5 (PGP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP) and tyrosine hydroxylase (TH). The ultrastructure of blood vessels supplying liver metastases and their perivascular innervation were also examined by transmission electron microscopy. In the normal liver, perivascular immunoreactive nerve fibres containing PGP, NPY and TH were observed around the interlobular blood vessels and along the sinusoids and the central vein of the hepatic lobule. The greatest density of immunoreactive nerve fibres was seen for PGP, followed (in decreasing order) by NPY and TH. VIP, SP and CGRP immunoreactivity was observed only in nerve bundles associated with the large interlobular blood vessels. In contrast, no perivascular immunoreactive nerves were observed in colorectal liver metastases. Electron microscopy confirmed the absence of perivascular nerves in liver metastases. In addition, it showed that the walls of these blood vessels were composed of a layer of endothelial cells surrounded by an incomplete or, very rarely in the periphery of the tumour, a complete, layer of synthetic phenotype of smooth muscle-like cells. These results imply that the blood vessels supplying liver metastases are bereft of normal neuronal regulation; whether there is a role for endothelial cell control of blood flow in these vessels is not yet known.     

Calcitonin, somatostatin and ACTH immunoreactive cells in a case of familial bilateral thyroid medullary carcinoma

Bilateral medullary carcinoma of the thyroid (MCT) was discovered in a symptomless patient of a high-risk MCT family. Raised serum calcitonin responding abnormally to pentagastrin led to a thyroidectomy. Grossly, the thyroid showed one nodule in the upper third of each lobe. Light microscopy revealed typical MCT with amyloid deposits. Nontumoral thyroid tissue showed C cell parafollicular hyperplasia. Electron microscopy detected intracellular secretory granules (mean diameter, 150 nm) and typical amyloid fibrills. Immunochemistry revealed numerous calcitonin immunoreactive cells in the nodules, in normal para and intrafollicular C-cells and hyperplastic C-cells. Somatostatin and ACTH were detected in certain tumor cells, but not in normal and hyperplastic C-cells. MCT hormonal production potential is discussed.     

Incorporation of [35S]sulfate in normal and neoplastic rat pancreatic acinar cells in relationship to cytodifferentiation

The rates of [35S]sulfate incorporation in highly differentiated acinar cells from normal pancreas, moderately differentiated cells of nafenopin-induced transplantable pancreatic carcinoma, and poorly differentiated cells from azaserine-induced transplantable pancreatic carcinoma were examined in an attempt to determine if sulfation is a property of acinar cells with well-developed secretory granules. The cells were dissociated, pulsed with [35S]sulfate (specific activity, approximately 1000 Ci/mmol) for 10 and 60 min, and chased with medium containing 100 X excess of cold inorganic sulfate for 0, 15, 60, and 120 min. The cells were then processed for determining their pool size and light and electron microscopic autoradiography. No significant differences among their pool sizes were observed. However, the light microscopic autoradiograms revealed the [35S]sulfate incorporation as follows: azaserine-induced transplantable pancreatic carcinoma greater than nafenopin-induced transplantable pancreatic carcinoma greater than normal pancreas. Electron microscopic autoradiograms revealed similar trends. The grain densities (concentration of radiation) were highest in the Golgi regions immediately postpulse (0 min) and gradually shifted toward the secretory granules over a 120-min period. In addition, the grain density values of the secretory granule-rich cells of nafenopin-induced transplantable pancreatic carcinoma were relatively similar to the cells of normal pancreas, whereas the grain density values of secretory granule-deficient cells from this tumor were similar to those of poorly differentiated neoplastic cells of azaserine-induced transplantable pancreatic carcinoma. These results show that poorly differentiated neoplastic cells incorporate more [35S]sulfate than do the well-differentiated cells, but the reasons for this unexpected differential incorporation are at present unknown.     

ACTH-secreting carcinoma of the breast.

We report a case of ACTH-secreting carcinoma of the breast. Membrane-bound secretory granules were seen within the cancer cells electron microscopically. Cytoplasmic granules reacting immunochemically to anti-ACTH antisera were seen on light microscopy. Breast cancers have been shown to secrete calcitonin, parathyroid hormone, human chorionic gonadotropin, and norepinephrine in addition to ACTH. This suggests either the presence of neuroendocrine cells in the breast as a source of such neoplasms, as in the lung, or genomic derepression during neoplastic transformation.     

Morphologic study of carcinoid-like tumors and their relation to true carcinoids, using tumors of the breast as a model

Two cases of an unusual type of infiltrating ductal carcinoma of the breast are presented. Both cases demonstrated a carcinoid-like pattern and were indistinguishable from carcinoid tumors of the breast by light microscopy. However, Grimelius stains and electron microscopic evaluation showed no evidence of membrane bound secretory granules. In regard to the prognostic significance and proper classification of carcinoids of the breast, awareness of carcinoid-like morphologic variants of infiltrating ductal or lobular carcinoma is important. It is also apparent that there is a spectrum of tumors which demonstrate some properties of true carcinoids, however, only the true carcinoids show a better prognosis and it serves no useful purpose to separate the rest of these tumors. The diagnosis of carcinoid tumors requires demonstration of secretory granules on electron microscopic examination or in special stains; conventional light microscopic studies alone are insufficient for this diagnosis. All these principles may be applied to carcinoid like tumors of other sites.     

Subtypes of T-cell chronic lymphatic leukemia

Thirteen cases of T-cell chronic lymphatic leukemia (T-CLL) (including T-cell prolymphocytic leukemia) are presented. Five subtypes were distinguished according to morphologic and functional parameters of the leukemic cells: prolymphocytic; lymphocytic, small; lymphocytic, Sézary-like; lymphocytic, abundant cytoplasm; lymphocytic, abundant cytoplasm and granules. The subtype can be recognized by light and by electron microscopic investigation. Cytochemistry (APh and ANAE) may be helpful to delimit T-CLL from B-CLL, and acid phosphatase to recognize the subtype characterized by abundant cytoplasm and granules. Membrane marker investigations support the diagnosis of T-type CLL. When functional properties of the leukemic cells were tested, cells of one patient (T-PLL) were shown to help in B-lymphocyte differentiation and Ig-secretion, whilst the cells of a second patient (lymphocytic, abundant cytoplasm and granules) were proven to act as effectors in natural killing and antibody-dependent cytotoxicity. The T-helper lymphocyte nature of some of the leukemic cells was supported by demonstration of the Fc mu-receptor in three cases. In one of these patients, monoclonal IgM was detected in the serum. Response to therapy and prognosis were rather poor in this limited number of patients when compared with B-CLL.     

Immunocytochemical evidence of molecular photoreceptor markers in cerebellar medulloblastomas

With the use of antisera against bovine retinal S-antigen and bovine opsin the authors demonstrate that in cerebellar medulloblastomas certain tumor cells display immunocytochemical properties characteristic of retinal photoreceptors and pinealocytes. S-antigen-like and opsin-like immunoreactions occur in nine of 28 medulloblastomas investigated. All tumors displaying S-antigen-like immunoreactive neoplastic cells also contain opsin-like immunoreactive cells; however, the opsin-like immunoreactive cells were less frequent than the S-antigen-like immunoreactive cells throughout all positive cases. The immunoreactive cells displayed several long processes. Generally, both S-antigen and opsin-like immunoreactive cells considerably vary in number among individual tumors. The results indicate that certain neoplastic cells of medulloblastoma are capable of expression of photoreceptor-specific proteins and, thus, may be closely related to tumor cells of retinoblastoma and pineocytomas previously shown to bind antisera against retinal S-antigen and opsin. No S-antigen and opsin-like immunoreaction was found in malignant teratomas and germinomas of the pineal gland, oat cell tumors, astrocytomas, ependymomas, oligodendrogliomas, glioblastomas, gangliogliomas, gangliocytoma, ganglioneuroblastomas, neuroblastomas, and esthesioneuroblastoma.     

Neuroendocrine Carcinoma of the Urinary Bladder: Case Report and Review of the Literature

A 63-year-old Japanese man complained of hematuria and pollakisuriafor several months. Computed tomography and cystography disclosedan infiltrative tumor mass in the irregularly thickened apicaland posterior walls of the urinary bladder. Narrowing of thevesical lumen and posterior extension of the tumor into thepelvic cavity were also noted. After palliative ureterocutaneostomy,60 Gy irradiation was given locally. The patient died of cachexiaseven months later. Autopsy revealed neuroendocrine carcinomaof the urinary bladder with extensive invasions and metastasesto the pelvic and peritoneal cavities, liver, lungs, vertebrae,left kidney and retroperitoneal lymph nodes. Histologically,atypical tumor cells with eosinophilic cytoplasm formed solidnests and anastomosing cords with pseudoglandular structures.No other histologic tumor components were included. An intacturachal remnant was found at the vesical apex while featuresof metaplastic cystitis were absent. In addtion to positivecarcinoembryonic antigen and cytokeratin, the argyrophilic cancercells were immunoreactive for neuron-specific enolase, chromograninA, serotonin, neuropeptide Y, glicentin, somatostatin, neurotensinand calcitonin. Ultrastructurally, neurosecretory-type granules,with a mean diameter of 166 nm, were identified in the cytoplasmof the tumor cells. To discuss the histogenesis of the tumor,44 previously reported cases of neuroendocrine carcinoma ofthe urinary bladder were reviewed.     

Characterization of the cellular component of polymorphous low-grade adenocarcinoma by immunohistochemistry and electron microscopy.

In order to characterize the cellular component of the polymorphous low-grade adenocarcinoma (PLGA) of the salivary gland, a morphological and immunohistochemical study was carried out. Thirty cases of PLGA were studied by light microscopy and immunohistochemistry and five cases by transmission electron microscopy (TEM). The expression of cytokeratins (CKs) 7,8,10,13,14,18,19, vimentin and muscle-specific actin (MSA) was investigated through the streptavidin-biotin method. The majority of tumor cells stained for vimentin, CKs 8, 18 and 7. CK 14 was positive in most cells of the papillary and trabecular sub-types. Although the expression of CKs 8,18 and 14 varied among the tumors sub-types, a straight relationship between each histologic pattern and the CK expression could not be delineated. MSA was reactive in only three tumors while CKs 10 and 13 were not detected in any tumor studied. The absence of MSA and the expression of CKs 8,18 and 7, in most of the tumor cells, lead to the hypothesis that myoepithelial cells are not the major cellular component of the PLGA. TEM revealed cells exhibiting microvilli and variable amounts of secretory granules, some of them suggesting an excretory activity. The presence of CKs 8,18 and 7, added to the secretory granules, indicates that PLGA originates from cells located at the acinar-intercalated duct junction.     

Immunohistochemical evidence of peptide hormones in endocrine tumors of the rectum

Twenty-five endocrine tumors of the rectum (rectal carcinoids) were examined immunohistochemically for various pancreatic and gut neurohormonal polypeptides. Twenty-one of the tumors were found to contain cells displaying pancreatic polypeptide (PP), glucagon, somatostatin, insulin, substance P, enkephalin or beta-endorphin immunoreactivity. At least 11 of the tumors contained more than one peptide hormone. In some of the tumors PP cells made up the major cell population, in others the glucagon cells constituted the majority. Only four of the tumors contained 5-hydroxytryptamine. Rectal endocrine tumors seem unique among gut endocrine tumors in that they may store immunoreactive enkephalin, beta-endorphin and even insulin. None of the patients displayed the carcinoid syndrome; symptoms were usually vague and uncharacteristic. In many cases the tumor was found at routine examination.     

Glucagonomas. Ultrastructure and immunocytochemistry

Pancreatic tumors harboring glucagon immunoreactive cells were found in four patients with diabetes mellitus. Alpha-cell (glucagon) granules were present in three tumors; pancreatic polypeptide (PP) immunoreactive cells were detected in two. In two patients the tumors were malignant and one of these had the glucagonoma syndrome; the other was a member of a family with MEN-type I syndrome. These cases illustrate three clinical subtypes of glucagonoma.     

Intramuscular myxoma. A clinicopathologic, immunohistochemical, and electron microscopic study

This clinicopathologic study concerns 17 cases of intramuscular myxoma, including an immunohistochemical survey of 10 cases and an electron microscopic examination of 4. There was a female preponderance in a ratio of 14:3. The most common sites of tumors were the large muscles of the thigh (seven cases), followed by those of the buttock (three) and the lower leg (three). The size of the tumor ranged from 1.5 to 20 cm (median, 6 cm) in the greatest diameter. Neither recurrence nor metastasis was seen in any of 15 patients for whom information was available. In addition to the conventional microscopic features, such as hypocellularity, absence of a plexiform capillary network, and no detection of typical glycogen-rich lipoblasts, the following findings were regarded as helpful to differentiate an intramuscular myxoma from myxoid liposarcoma: hypovascularity of the tumor, demonstrated by angiography; a homogeneous computed tomography appearance with low density, absence of S-100 protein immunoreactive cells such as lipoblasts; and electron microscopically, the constituent cells were predominantly fibroblast-like cells with a prominent secretory activity, together with a small number of primitive mesenchymal cells and histiocyte-like cells, but with no lipoblasts. After simple excision, the 15 patients who could be followed are well with no recurrence during various periods of follow-up.