Argyrophilic Granules Research Articles

Heterotransplantation of argyrophil small cell carcinoma of the uterine cervix integrating HPV16 DNA into nude mice.

Argyrophil small cell carcinoma of the uterine cervix (ASCC) containing human papillomavirus type 16 (HPV16) DNA has been successfully transplanted in nude mice for the first time, and we have designated the resultant cell line as YIK‐1. Histology of YIK‐1 was similar to that of the original tumor. The original and YIK‐1 tumor cells contained argyrophil granules and neurosecretory granules in the cytoplasm, and were immunohistochemically stained positive for neuron‐specific enolase, serotonin and chromogranin. Both tumors contained HPV16 DNA in a multiple‐copy integrated form. Thus, YIK‐1 maintains the characteristics of the original ASCC, and may therefore be useful as an animal system for experimental studies of ASCC.

Medullary (C cell) carcinoma of the thyroid with features of follicular oxyphilic cell tumours

During the last few years the spectrum of histological features seen in tumours of C cell origin has broadened and, among other variants, papillary and glandular forms have been recognized. Seven cases are now reported of medullary carcinoma with features of oxyphilic follicular cell tumours. These cases were studied with routine techniques and an immunolocalization method using antibodies to calcitonin and thyroglobulin. The tumours were mainly composed of well-demarcated eosinophilic cells of variable size arranged in trabecular, solid and follicular structures. One of the cases was negative for calcitonin but displayed strong diffuse argyrophilia and amyloid deposits; two amyloid-free tumours revealed argyrophil granules and were positive for calcitonin, the immunoreaction being inconspicuous in one however. Apart from trapped normal thyroid follicles, thyroglobulin was absent in the tumours. It is concluded that medullary carcinoma should be considered in the differential diagnosis of thyroid oxyphilic cell tumours, even when showing glandular differentiation, and that immunolocalization techniques using calcitonin and thyroglobulin in combination with methods for demonstration of argyrophil granules and amyloid are essential for accurate diagnosis of this type of medullary carcinoma of the thyroid.

Endoscopic diagnosis of a duodenal gastrinoma

A 50-year-old man with a 6-year history of diarrhea following vagotomy and pyloroplasty was admitted to an outside hospital to evaluate for presence of ZES. Relevant abnormal test results included a serum gastrin of 515 pg/ml (normal, <200 pg/ml) and fecal fat of 25 g/day. The n-xylose test was normal. Esophagogastroduodenoscopy (EGD) revealed thick gastric folds and prominent duodenal folds. Duodenal mucosal forceps biopsies showed chronic inflammation. The patient was transferred to the Veterans Administration Medical Center where a basal acid output of 21 mEq of hydrogen ion per hour was found by gastric analysis. Stimulation with 2 mg/kg of KABI secretin caused an increase in serum gastrin from a baseline value of 263 pg/ml to 451 pg/ml and 482 pg/ml at 5 and 10 min, respectively. EGD confirmed the previously described findings but in addition showed mild antritis, erosive duodenitis, an 8-mm post bulbar ulceration, and a 1.0-cm sessile lesion with a central depression on the lateral wall of the second portion of the duodenum (Fig. 1). Multiple endoscopic forceps biopsies of this lesion were performed. Histopathology revealed a minute focus of islet cell tumor in the lamina propria in one of six specimens. The tumor cells were regular, round, arranged in an insular pattern with focal glandular differentiation, had pale eosinophilic cytoplasm, and round to oval hyperchromatic nuclei with uniformly distributed punctate chromatin characteristic of neuroendocrine tumors (Fig. 2). Grimalius stain was positive for argyrophilic granules and immunoperoxidase stain, specific for gastrin, was strongly positive in the cytoplasm of many cells (Fig. 3). Abdominal computed axial tomography was unremarkable. The patient was transferred to the National Institutes of Health where abdominal ultrasound and magnetic resonance imaging of the liver and pancreas were normal. Angiography showed a hypervascular blush in the pancreatic head and spleen, but the significance of this latter finding could not be confirmed at laparotomy. A 1.0-cm islet cell tumor in the posterior portion of the head of the pancreas and the 1.0cm duodenal gastrinoma were resected. Fasting postoperative gastrin levels were 97, 66, and 121 pg/ml on three separate occasions. Postoperative basal acid output was low and a secretin stimulation test negative.

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We describe three cases of intravagal paraganglioma and review the literature on clinical and histological findings and treatment. Our patients ranged in age from 36 to 46 years (mean, 40 years old); two males and one female.All three patients had a large parapharyngeal mass, and paralysis of the reccurent laryngeal nerve was noted in two of them. At surgery the tumors were found to be very close to the vagus nerve. However, the carotid bifurcation was not widened. Postoperative irradiation (60 Gy) was performed in one case because the tumor was unresectable. All tumors demonstrated similar histological characteristics. They were highly vascularized and had prominent hyalinized collagenous septa. An alveolar pattern was produced by the reticulin network. Each tumor cell had an ovoid or round nucleus and eosinophilic cytoplasm. Cytoplasmic argyrophil granules were demonstrated by the Grimelius stain, proving the tumors to be paragangliomas.

Congenital polycystic tumor of the atrioventricular node (endodermal heterotopia, mesothelioma): A histogenetic appraisal with evidence for its endodermal origin

The small, variously designated, primary atrioventricular node tumor has been considered to be of endothelial, endodermal, or mesothelial origin. To identify its derivation, we studied seven tumors using silver staining and immunocytochemical labeling with a variety of antibodies. Cytoplasmic argyrophil granules but not argentaffin granules were found in isolated cells among the more numerous tubule-lining cells in four tumors. Serotonin and calcitonin were demonstrable in seven and six tumors, respectively, in a similar distribution to that of the argyrophil cells. A positive reaction of different distribution from that of the argyrophil cells was noted in a varying number of tubule-lining cells for carcinoembryonic antigen, epithelial membrane antigen, and blood group antigen in seven, four, and seven tumors, respectively. No activity was noted in the tumor cells for factor VIII-related antigen or a number of peptides. An endodermal rather than mesothelial or epithelial origin for the tumor is substantiated by the presence of neuroendocrine cells in the midst of the more numerous carcinoembryonic-antigen-positive lining cells of the tumor tubules.

Pathologic features of abdominal and thoracic paragangliomas in F344/N rats.

Seventeen paragangliomas were identified in a retrospective review of 200 NTP/NCI carcinogenicity studies in F344/N rats that served either as control or treated animals. Most tumors were grossly visible and located in the retroperitoneum adjacent to the vertebrae and aorta near the kidneys. Three microscopically detected paragangliomas were found at the base of the heart. Microscopically, neoplastic cells were in nests separated by reticulin fibers and capillaries. Argyrophil granules were in the cytoplasm of the retroperitoneal and mediastinal paravertebral tumors. Dense granules were found in the one tumor examined ultrastructurally. Some tumors had areas of necrosis and tumor emboli were present in the lumen of the abdominal aorta and vena cava adjacent to the tumor with metastases present in pulmonary vessels. The incidence of retroperitoneal neoplasms was 3 times more frequent in male than in female F344/N rats.

Solid and papillary epithelial neoplasm of the pancreas. An ultrastructural and immunocytochemical study of six cases.

Solid and papillary epithelial neoplasms of the pancreas from six female patients were studied using immunohistochemistry and electron microscopy to define better their histogenesis. The tumors ranged in diameter from 5 to 15 cm (average: 9 cm), and, on cross section, most had areas of hemorrhage and necrosis, sometimes extensive. Microscopically, there was a solid and pseudopapillary pattern, with tumor cells typically having ovoid nuclei with delicate folding and indistinct nucleoli. Of note were the following: a relatively low mitotic rate (range: 0-6/20 hpf), the presence of hyaline globules (four of six cases), and collections of foam cells (three of six cases). Staining for cytoplasmic argyrophil granules was negative in each case. Ultrastructurally, the solid and papillary epithelial neoplasms of the pancreas showed evidence of acinar or ductular differentiation. Two contained zymogen granules, one had intermediate filaments (probably keratin), and three had abundant rough endoplasmic reticulum and mitochondria. Immunostaining was positive for chymotrypsin (six of six cases), trypsin (four of six), and amylase (three of six). None was positive for alpha-1-antitrypsin, neuron-specific enolase, pancreatic polypeptide, gastrin, glucagon, somatostatin, or insulin. The findings support an origin from exocrine pancreas, and follow-up indicates a low rate of malignancy, with local recurrence in two of the six patients.

Argyrophil cells in normal endometrial glands.

Normal endometrium from one hundred normal cases were examined histologically, using sections stained with the Grimelius method. Endocrine cells were demonstrated in 4 cases. Immunohistochemically, these cells were positive for anti-serotonin and anti-somatostatin antisera. Argyrophil granules were also observed in supranuclear or subnuclear regions of glandular cells in 17 cases, and argyrophilia was present in the apical region including the brush borders or microvilli of glandular cells in 6 cases. In these latter 23 cases argyrophilia seemed to be nonspecific, having no relation to endocrine type secretory granules, judging from the electronmicroscopic observations on the silver-impregnated sections. The presence of endocrine cells and the pattern of argyrophilia in glandular cells were similar to those found previously in endometrial glandular adenocarcinomas with argyrophil cells. This is the first report on the occurrence of endocrine cells in normal endometrial glands.

Presence of cells with argyrophil granules in normal, hyperplastic, and neoplastic endometrium.

Cells with argyrophil granules were searched for in 131 consecutive specimens obtained from endometrial curettage. Particular care was taken with the fixation methods to avoid a false positivity to the silver impregnation according to Grimelius. We did not consider the grossly argyrophilic positivity on the cellular apex or of the whole cytoplasm, which was partially reduced by diastase digestion and probably due to the presence of glycogen and secretory mucoproteins. Cells with thin argyrophilic granules similar to those observed in endocrine APUD cells were present among glandular cells and/or among stromal cells in 15 of 131 examined specimens. They concerned 5 cases of proliferative endometrium, 3 of secretive endometrium, 5 of hyperplasia, and 2 of carcinoma. In 8 of the 15 cases with argyrophilic cells, immunohistochemical studies with the PAP method showed cells with the presence of FSH, S-100 protein, somatostatin, vasoactive intestinal peptide (VIP), gastrin, and neuron-specific enolase (NSE). The significance and origin of these cells in normal and neoplastic endometrium are discussed.

Clinical significance of argyrophilia in endometrial carcinomas

The clinical significance of argyrophilia in endometrial carcinomas was studied in 187 patients with the endometrioid form of adenocarcinoma. Argyrophil cells were tentatively subgrouped into two types: type I cells resembling the enterochromaffin cells and type II cells loaded with argyrophil granules in the apical portion or throughout the cytoplasm. The patients with endometrial carcinoma containing argyrophil cells were associated more frequently with hypertension and diabetes mellitus than those with usual endometrial carcinoma. In grade 1 carcinomas, argyrophilia was parallel with the frequency of metastases to lymph nodes and with the degree of myometrial invasions. Also, a life table showed a worse survival rate in grade 1 carcinomas with argyrophilia, especially of type I, than in those without it. Although argyrophilia was considered to be at least one of the minor prognostic factors, further clinicopathologic studies are needed in relation to a more proper subtyping of argyrophil cells.

Immunohistochemical demonstration of chromogranin in endometrial carcinomas with argyrophil cells

Forty-five endometrial carcinomas, 36 of which contained argyrophil cells and nine of which were nonargyrophilic by the Grimelius method, were examined immunohistochemically for chromogranin. Chromogranin immunoreactivity was present in 19 of the 36 tumors with argyrophil cells (53 per cent) and in none of the nine tumors lacking these cells. All six of the tumors that contained argyrophil cells resembling enterochromaffin cells were chromogranin-positive, with the staining corresponding to the argyrophilia. In contrast, only 13 of the 30 tumors in which argyrophilia was present in the apical region or throughout the cytoplasm of the cells showed chromogranin immunoreactivity. In seven of these tumors, an excellent correlation existed between the distribution of argyrophilia and chromogranin positivity, but in the other six tumors argyrophilia was more pronounced than chromogranin immunoreactivity. Adjacent to one tumor, unusual cells in which argyrophil granules were packed predominantly in the basal portion of the cytoplasm were encountered in a focus of atypical hyperplasia; these cells were also chromogranin-positive. The present observations suggest that endometrial carcinoma cells with diffuse or apical chromogranin immunoreactivity may represent an early stage in the development of cells resembling those of the enterochromaffin type.

Argyrophilic Cells In 202 Human Mucinous Breast Carcinomas: Relation to Histopathologic and Clinical Factors

Two hundred two human, mucinous breast carcinomas were investigated for the presence of argyrophilic granules, and these granules were found in 25% of the cases. The granules were located in the cytoplasm and were heterogeneously distributed within the tumors. Tumors with granules were otherwise morphologically indistinguishable from those tumors without granules. The recurrence-free survival was independent of the presence of granules, and no relation was found to other clinical or histopathologic factors. Tumors with granules were found to be estrogen-receptor positive, and they appear to have a slightly less aggressive growth pattern than tumors without granules, but the difference is far from being statistically significant. It is concluded that there is no convincing evidence that this group of primary breast carcinomas with argyrophilia originates from APUD cells.

Ovarian strumal carcinoid tumor with amyloid stroma—Report of a case with 20-year follow-up

We report a case of strumal carcinoid tumor arising in the left ovary of a 20-year-old woman. Histologically, microfollicular, solid, and trabecular areas were present, and amyloid stroma was demonstrated. Many cells contained argyrophilic granules, and thyroglobulin and calcitonin were demonstrated immunohistochemically in several areas. Ultrastructurally the cells resembled thyroid follicular cells and contained neurosecretory granules. It is concluded that strumal carcinoid is of endodermal origin, and shows evidence of thyroid and C-cell differentiation.

Paraganglioma of the cauda equina: A histological, ultrastructural and immunocytochemical study of two cases with a review of the literature

The clinical and pathological features of two paragangliomas arising in the cauda equina are described and compared with 14 previous reports. The light microscopic features were similar to those of paragangliomas from other sites, with a 'Zellballen' pattern of cells containing argyrophil granules. Electron microscopy showed densely staining membrane-bound granules, cilia and fibrous bodies in the cytoplasm. The last two features only occur in paragangliomas from this site. gamma-Enolase was demonstrated by the peroxidase-antiperoxidase technique for the first time in these neoplasms. This technique was also used to demonstrate cytokeratins, which appear to be associated with the presence of fibrous bodies. The pathological findings suggest that paragangliomas in this site arise from pre-existing paraganglia, possibly of the visceral autonomic group. The prognosis in cases treated by complete excision appears to be good.

Ultrastructural Characteristics and Variations in Human Mutinous Breast Carcinomas

Nineteen human mucinous breast carcinomas have been studied by electron microscopy in order to investigate the variations in the fine structure of this type of tumor. All the investigated tumors are characterized by a well-developed, rough endoplasmic reticulum and prominent Golgi complexes. The majority of tumor cells contain secretory granules. Approximately 50% (9/19) of the tumors have cytoplasmic dense core granules that are morphological identical to the neurosecretory granules found in APUD-cell derived tumors. Six out of the nine tumors react positively in a Grimelius staining for light microscopic argyrophilic granules. Two of the investigated breast carcinomas contain tonofilaments that are normally regarded as characteristic of squamous epithelium. It is concluded that mucinous breast carcinomas--that to this time have been regarded as a morphological homogenous group of tumors--are ultrastructurally characterized by heterogeneity.

Immunohistochemical demonstration of peptide hormones in endometrial carcinomas.

Sixty-eight endometrial carcinomas were examined histochemically and immunohistochemically for the presence of amine-containing or neurohormonal peptide-containing cells, particularly in relation to argyrophil cells. Argyrophil cells, detected in 43 of the 68 endometrial carcinomas by the Grimelius method, were subgrouped into two types according to the distribution of argyrophil granules and the shape of the tumor cells. Type I was found in 7 tumors and type II in 39; 3 tumors contained both cell types. The argyrophilia of type II cells was diminished in varying degrees in some tumors by diastase digestion, although it was unchanged in type I argyrophil cells. Indoleamine was detected by the formaldehyde-induced fluorescence method in type I argyrophil cells of four carcinomas. Immunohistochemically, somatostatin-reactive cells were found in two well-differentiated adenocarcinomas with argyrophilia; many of these cells corresponded to some of the type I argyrophil cells, although some were non-argyrophilic. Two adenosquamous cell carcinomas with type II argyrophil cells also contained cells that were immunoreactive with antisera against gastrin; however, they were non-argyrophilic.

Argyrophil cells in the endometrioid carcinoma of the ovary.

Of 42 endometrioid carcinomas of the ovary examined with Grimelius staining, 19 tumors were found to have argyrophil cells. Argyrophil cells were subgrouped into two types according to the distribution of the argyrophil granules. Type I cells contained argyrophil granules in the basal part of the cytoplasm, and were found in four tumors. Type II cells contained argyrophil granules mainly in the apical portion or throughout the whole cytoplasm, and were found in 14 tumors. Both type I and II cells were found in different areas of one tumor. In type II cells, the distribution of argyrophil granules was similar to that of mucins, and the apical argyrophilia was diminished in varying degrees in some tumors after diastase digestion. The distribution of argyrophil granules paralleled that of secretory granules identified by electron microscopy in the representative tumors of each type. In the immunohistochemical study, somatostatin was found in a tumor with both types of argyrophil cells. Somatostatin-containing cells generally corresponded to type I cells, but were less numerous than argyrophil cells.

Endocrine carcinoma intermediate cell type of the uterine cervix

Nine cases of endocrine carcinoma, intermediate-cell type of the uterine cervix, were found in a study of 404 cases listed in the files of the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston as adenocarcinoma of the cervix. Based on light microscopic patterns, these cases were divided into pure endocrine carcinoma (six cases), and endocrine carcinoma mixed with adenocarcinoma (three cases). All tumors were 3 cm or larger in at least one dimension. On light microscopic examination, the predominant pattern was trabecular; however, insular, glandular, and spindle patterns were also identified. Argyrophilic granules were demonstrated in all cases by Grimelius stain, and Fontana-Masson (argentaffin) stain was negative. Electron microscopic examination of three cases showed membrane-bound, dense-core granules of the neurosecretory type. Although no endocrine symptoms were found, immunoperoxidase studies demonstrated 5-hydroxytryptamine in seven cases, substance P in three, vasointestinal polypeptide in two, pancreatic polypeptide in one, and somatostatin in one. Clinical behavior of these tumors was extremely aggressive. Although five cases were Stage IB at presentation, two Stage IIB, one Stage IIIB, and one Stage IV, 87.5% of these patients died of their neoplasms within 3 years. This study emphasizes the importance of correctly diagnosing endocrine carcinoma, intermediate-cell type in the uterine cervix, because of the poor prognosis of this tumor when compared with adenocarcinoma of the cervix.

Production of immunoreactive-polypeptide hormones in cervical carcinoma.

The levels of immunoreactive-polypeptide hormones were measured in tissue extracts of eight uterine cervical cancers by specific radioimmunoassays. In one case with argyrophil granules, high levels of somatostatin, pancreatic polypeptide, calcitonin, and vasoactive intestinal polypeptide (VIP) were found, ranging from 160 to 880 ng/g tissue. A second argyrophil cancer contained 310 ng/g tissue of somatostatin, and a third contained 1100 ng/g tissue of adrenocorticotropic hormone (ACTH) and 380 ng/g of beta-melanocyte-stimulating hormone (beta-MSH). In addition, of the five nonargyrophil cancers tested, four contained calcitonin, three had VIP, two had either somatostatin or glucagon, and one contained ACTH and beta-MSH; the measured levels of these hormones ranged from 1.4 to 2.3 ng/g tissue. Gel filtration on a Sephadex G-75 column showed that the immunoreactive-polypeptide hormones in the first case were chromatographically similar to the authentic or prehormones. These results indicate that ectopic production of multiple immunoreactive-polypeptide hormones is common not only in argyrophil cell carcinoma, but also in nonargyrophil cell carcinoma of the cervix.

Quantitative and immunocytochemical studies of APUD cells in airways and gut. The effects of priming with L-dopa and 5-HTP.

The amine precursor uptake and decarboxylase (APUD) cells in airways and small intestine of adult hamsters have been studied by quantitative, histochemical and immunocytochemical methods for the presence of argyrophilia, ACTH, hGH, calcitonin, bombesin and prolactin in control animals and following priming with two amine precursors: L-dopa and 5-hydroxytryptophane (5-HTP). APUD cells have been defined by the presence of intracytoplasmic argyrophilic granules. A method that related them to airway or gut perimeter length or total epithelial cell numbers has been applied. Calcitonin-like-immunoreactivity (CLIR) is present in epithelial cells in the tracheal epithelium and glands. The presence of ACTH, hGH, bombesin or prolactin is not detected. Priming with L-Dopa and 5-HTP results in up to 12 fold increases in densities of argyrophilic APUD cells in airways and ileum when ratios of APUD cells/100 nuclei are compared to those in control animals. Exposure to 5-HTP induces no significant changes in densities of cells with CLIR in the trachea but CLIR is not detected in animals exposed to L-DOPA. Ratios of APUD cells/100 epithelial cells appear to be more sensitive than those of APUD cells/mm in detecting significant changes in APUD cell densities. Priming with amine precursors is a valuable tool in quantitative studies of neuroendocrine cells.