Bronchial glomus tumor mimicking a COPD exacerbation.

We report the case of a glomus tumor originating in the left main bronchus diagnosed in a 79 year old Caucasian man. A glomus tumor is an extremely rare neoplasm in the bronchi with nonspecific clinical features. Bronchoscopy allows the diagnosis through biopsy and subsequent histopathological examination of the tissue and in selected cases may represent a valid alternative to surgery permitting a radical tumor excision.

Kikuchi's disease: an uncommon cause of fever of unknown origin.

Kikuchi's disease or histiocytic necrotizing lymphadenitis is an uncommon clinical condition that causes diagnostic difficulties because of its lack of specific signs, symptoms and serological markers. Diagnosis is based on histopathological findings, but overlapping of the histological features requires a differential diagnosis among histiocytic necrotizing lymphadenitis and a number of infectious, autoimmune and lymphoproliferative lymphadenopathies. We report a case of Kikuchi's disease in a 19-year-old woman presenting with generalized lymphadenopathy and persistent fever.

Quantitative analysis of apoptosis and bcl-2 in Sjögren's syndrome.

OBJECTIVE: To determine whether apoptosis plays a significant role in tissue damage of Sjögren's syndrome (SS). METHODS: We performed a quantitative analysis of programmed cell death on salivary glands of 11 patients. Ten age matched women with sicca syndrome served as controls. Morphometric measurement of the fractional volume of acini and ducts showing DNA strand breaks was performed in sections stained by deoxynucleotidyl transferase assay. The extent of bcl-2 expression was determined in sections labeled with monoclonal antibody. The different cell populations infiltrating the glands were examined in tissues stained with anti-leukocyte common antigen and OPD4 monoclonal antibodies. RESULTS: In patients with SS, 68% of the ductal epithelium was occupied by apoptotic structures, whereas only 12% of acini showed DNA strand breaks. Corresponding values in control salivary glands were 3 and 0.13%. bcl-2 labeling was higher in ducts than in acini of both control and pathologic glands. However, in SS a 43% (p < 0.001) and 75% (p < 0.001) reduction in bcl-2 expression was observed in ductal and acinar epithelium, respectively. In comparison with controls, the numerical density of CD4+ cells and plasma cells scattered throughout the interstitium was 323% and 203% higher (p < 0.001) in SS. Moreover, T helper/inducer lymphocytes represented 52% of the inflammatory foci. CONCLUSION: Apoptosis occurs in minor salivary glands of patients with SS with a prevailing localization on the ductal epithelium in association with downregulation of bcl-2 and a large number of infiltrating CD4+ lymphocytes. Thus, the destruction of glandular tissue and the loss of secretory function in SS is dependent on the activation of the suicide program of epithelial cells.

Neuroendocrine proliferation in the gastric mucosa: biological behaviour and management.

Neuroendocrine proliferation of gastric mucosa is commonly encontered in routine gastric biopsies and is an indirect effect of modern drugs suppressing acid secretion. The process is virtually circumscribed to the ECL cell, the most common endocrine cell of the oxyntic mucosa, and is dependent on the trophic effect of the concomitant hypergastrinemia in most cases. It starts in the form of hyperplastic lesions that in some cases evolves into dysplasia and neoplasia. Gastrin has promoting but not transforming properties for such ECL cell tumour induction. Proven or potential transforming factors include the allelic loss of the MEN-1 suppressor gene at 11q13, the still unknown factor(s) associated with atrophic corporal gastritis in which overexpression of BCL-2 likely plays a favouring role by prolonging ECL exposure to mitogens, and agents with still unclarified role, such as basic fibroblast growth factor, human chorionic gonadotropin-alpha and transforming growth factor-alpha. Gastric neuroendocrine tumours independent of the trophic effect of gastrin are less frequent but more malignant. Their pathogenesis and precursor lesions are ignored.

Dual therapy with high or low doses of omeprazole does not achieve an acceptable rate of Helicobacter pylori eradication in duodenal ulcer patients. A multicentre randomized long-term detailed study.

BACKGROUND: It has been reported that dual therapy with high doses of omeprazole and amoxycillin proves efficient for Helicobacter pylori eradication. AIM: To compare the efficacy, safety and tolerability of eradicating regimens with omeprazole/amoxycillin. METHODS: In this randomized multicentre study, 267 duodenal ulcer patients were treated for 2 weeks with omeprazole 40 bid (Group A) or 20 mg bid (Group B), respectively, and with amoxycillin 0.5 g. qid followed by 4 weeks of 20 mg omeprazole om. Helicobacter pylori status was assessed by both histology and urease test in the antrum and the corpus. The patients were then followed-up for 9 months. RESULTS: Helicobacter pylori infection was cured in 62.9% of group A (95% CI: 53.8-71.4) and in 44.8% of group B (95% CI: 35.6-54.3; p = 0.007). Healing was achieved in 91.9% of patients in group A (95% CI:85.7-96.1), and in 87.9% of patients in group B (95% CI:80.6-93.2). The estimated probability of being in ulcer remission for cured patients was 0.95 (95% CI: 0.90-0.99) and for the not cured was 0.41 (95% CI: 0.24-0.59; p = 0.0001). However, between the two treatment groups no significant differences in symptom relief or ulcer recurrence were observed. Both regimens were well tolerated with minor side-effects occurring likewise within the two groups. At two months in cured patients antral histology revealed a total (group A + B) prevalence of 13.7% of active chronic gastritis. CONCLUSIONS: This long-term, large-size study clearly indicates that dual therapy does not represent a truly effective eradication therapy and this regime cannot be recommended.

Nuclear grading and flow cytometric DNA pattern in fine-needle aspirates of primary breast cancer.

Fine-needle aspiration (FNA) biopsy is increasingly used in the diagnosis and biological characterization of breast carcinomas in patients who receive preoperative chemotherapy. In this context, nuclear cytologic grade supplemented by DNA content could play an important role in the morphologic assessment of breast cancer. In this study, DNA ploidy pattern, analyzed by flow cytometry on FNAs from 92 primary breast carcinomas, was related to cytologic nuclear grade. Twenty-seven samples were cytologic grade 1, 33 were grade 2, and 32 were grade 3. Ploidy correlated with cytologic nuclear grade (P = 0.0001). Thirty percent of grade 1, 55% of grade 2, and 84% of grade 3 tumors were DNA aneuploid. For 30 of the 92 FNAs, it was possible to compare nuclear cytologic grade with the corresponding histologic grade using the Scarff, Bloom, and Richardson system. A high concordance (80%) between nuclear grade on FNAs and histologic grade was found. DNA flow cytometry in combination with nuclear cytologic grade might represent additional information for the characterization of breast cancer diagnosed by FNA.

Hypergastrinemia and gastric enterochromaffin-like cells.

The enterochromaffin-like (ECL) cell of the oxyntic, acid-secreting mucosa is at present the most extensively studied endocrine cell type in the gastrointestinal tract. It is functionally related to acid secretion through paracrine release of histamine. Its ability to undergo proliferation in response to the trophic stimulus of hypergastrinemia has important implications in pathology, being involved in the development of ECL-cell carcinoid tumors of rodents treated with powerful inhibitors of acid secretion as well as in that of most human gastric carcinoids which, with rare exceptions, are composed of ECL cells. The various aspects of the ECL-cell response to hypergastrinemia in humans are discussed in this review. The trophic effect of gastrin is specific for ECL cells and its sensitivity is enhanced by the female sex and by the genetic background of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Exposure of ECL cells to hypergastrinemia induces peculiar changes in the structure of cytoplasmic granules and triggers the phenotypic expression of a novel protein, the alpha subunit of glycoprotein hormones, absent in normal cells. The ECL-cell hyperplasia driven by hypergastrinemia may influence the hypersecretory gastric state of patients with Zollinger-Ellison syndrome (ZES) by inappropriate intramucosal secretion of histamine and may contribute to the high circulating levels of basic fibroblast growth factor (bFGF), an ECL-cell product responsible for parathyroid mitogenic effects in MEN-1 patients. However, hypergastrinemia per se cannot promote evolution of hyperplasia into carcinoid tumors, for which additional unknown factors, particularly associated with atrophic gastritis or MEN-1 syndrome, are required. ECL-cell carcinoids developing within these backgrounds have a strikingly more favorable course than their gastrin-independent counterpart. Suppression of hypergastrinemia, either by antrectomy or treatment with somatostatin analogues, may induce regression of both ECL-cell hyperplasia and gastrin-sensitive ECL-cell carcinoids.

Gastric carcinoid tumor and its precursor lesions. Ultrastructural study of a case before and after antrectomy.

Antrectomy has been proposed as the preferential treatment of hypergastrinemic patients with nonantral gastric carcinoids since it removes the main growth factor for the tumors and their precursor lesions, ie, hypergastrinemia. To investigate the cellular basis of the mechanism for postantrectomy regression in nonantral endocrine cells, a light and electron microscopic morphometric study was performed in a case of enterochromaffinlike-cell gastric carcinoid associated with hypergastrinemia before and 4 and 10 months after antrectomy. The withdrawal of sustained hypergastrinemia obtained by antrectomy was associated with a progressive reduction of the volume density, cross-sectional area, and number of profiles of endocrine cells in the remaining nonantral mucosa, in which gastrin-dependent proliferations were regarded as the carcinoid precursor lesions. Ultrastructural morphometry demonstrated that the changes selectively involved the enterochromaffinlike cells, ie, the specific cell target for the trophic action of gastrin and the usual component of gastric carcinoids. The volume fractions of enterochromaffin and X cells (producing serotonin and endothelin, respectively) were increased 10 months after antrectomy. Persistence of a modest elevation of gastrin levels, likely due to the occurrence of gastrin cells in areas of pyloric metaplasia of the nonantral mucosa, did not prevent the hypotrophic effects of antrectomy.

Three months of octreotide treatment decreases gastric acid secretion and argyrophil cell density in patients with Zollinger-Ellison syndrome and antral G-cell hyperfunction.

METHODS: The effects of three months of treatment with octreotide on gastric acid hypersecretion induced by hypergastrinaemia were investigated in patients with Zollinger-Ellison syndrome (n = 5) or antral G-cell hyperfunction (n = 4). Gastric acid secretion, fasting plasma gastrin concentrations and clinical findings were examined, and a morphometrical analysis of oxyntic endocrine cells was performed. RESULTS: Administration of octreotide 100 mcg b.d. subcutaneously significantly decreased the volume density of argyrophil cells (P < 0.05) as well as basal and pentagastrin-stimulated acid secretion (P < 0.05). Although partial or complete loss of inhibition was found in most patients after 3 months, gastrin levels were decreased during the first 2 months of treatment (P < 0.05). Fundic D-cells were not affected by treatment. Positive correlations were observed between volume density of argyrophil cells and basal acid output (r = 0.65); plasma gastrin and basal acid output (r = 0.74); plasma gastrin concentrations and volume density of argyrophil cells (r = 0.80). CONCLUSION: These results support the important role of the enterochromaffin-like cell in maintaining acid secretion, and indicate a specific role for octreotide in the therapy of gastric acid hypersecretion associated with hypergastrinaemic diseases.

[Stereotactic fine-needle aspiration biopsy (FNAB) of nonpalpable breast lesions: cyto-histological correlations]. / Agoaspirazione (FNAB) mediante centratura stereotassica di lesioni mammarie non palpabili: correlazioni cito-istologiche.

There are not complete consensus if mammographically guided FNABs of nonpalpable breast lesions can replace open biopsy. To elucidate this problem, we have reviewed the efficacy of stereotactic FNAB in a series of 502 cases of nonpalpable lesions observed in a period from 1990 to 1994, with a immediate cytologic control of adequacy of material. In 144 patients of the lesion is achieved with 4% sterile coal localisation and an open biopsy of the area performed. In each case cytologic findings, with a brief description of probable histotype of the lesion, are correlate with surgical pathologic diagnosis, with a comparison between two time period (1990-92; 1993-94). In our study particularly ductal and lobular hyperplasia (with or without atypia) restrict the efficiency of the FNAB. In fact the specificity varies from 83.3% to 90.3%, the sensitivity from 78.7% to 77.8%, positive predictive value from 86.0% to 90.3%, negative predictive value from 75.6% to 70% and diagnostic accuracy from 80.0 to 82.4%, considering ductal and lobular hyperplasias as true negatives or true suspects. Cytologically we have 2 false positive in the first period of time, 3 false suspects in the second period of time and 7 false negatives. However benign/malign biopsy ratio is well (0.97). Moreover histopathologic informations of cytological diagnosis is variable according the histotype of the lesion. In conclusion our study confirm that FNAB is an reliable method that avoid unnecessary biopsy but is insufficiently sensitive to replace open biopsy of nonpalpable breast lesions, also with an immediate cytological control of adequacy of aspirate.

Morphometry of gastric endocrine cells in hypergastrinemic patients treated with the somatostatin analogue octreotide.

The aim of the study was to evaluate whether treatment with 200 micrograms/d of the somatostatin analogue octreotide (SMS 201-995) for three months can influence the trophic action exerted by hypergastrinemia on endocrine cells of the oxyntic mucosa, a condition potentially leading to hyperplasia and carcinoid tumors. Endocrine cells were morphometrically investigated in Grimelius silver stained sections of endoscopic biopsies of oxyntic mucosa collected from 13 hypergastrinemic patients with Zollinger-Ellison syndrome (ZES) (n = 5), antral G cell hyperfunction (AGCH) (n = 4) and atrophic gastritis type A (AG-A) (n = 4) before and after 3 months treatment and 3 months after drug discontinuance. The treatment induced a reduction of the volume density (P < 0.015), profile cross sectional area (P < 0.05) and number of cell profiles per unit area (P < 0.015) of argyrophil cells. A rebound of all these parameters was observed 3 months after drug withdrawal with values usually exceeding those at the entry, except in cases of AG-A. The patients' plasma gastrin concentrations presented similar variations showing a significant relation with all morphometric parameters of argyrophil cells. Also, the cell content in alpha subunit of human chorionic gonadotropin was related to the plasma gastrin levels, a finding confirming the close gastrin dependence of the expression of this protein by oxyntic endocrine cells. No significant changes were observed in mucosal somatostatin D cells. These results indicate that variations in circulating gastrin levels are the most likely factor responsible for the hypotrophic effect of octreotide on oxyntic argyrophil cells (mostly corresponding to the ECL cells) of hypergastrinemic patients.

Ultrastructural morphometry of gastric endocrine cells before and after omeprazole. A study in the oxyntic mucosa of duodenal ulcer patients.

Long-term toxicological experiments with inhibitors of acid secretion were found to induce hyperplasia and eventually carcinoid tumors of the enterochromaffin-like cells of the oxyntic mucosa. To evaluate the effects of 6 months' treatment with omeprazole in humans, the oxyntic endocrine cells were morphometrically investigated at the ultrastructural level in five patients with active duodenal ulcer. No omeprazole-induced changes were found in the volume density of the total endocrine cell population and specific cell types (including the enterochromaffin-like cell) as well as in the other cytological parameters investigated (number of cell profiles per unit area, mean cross-sectional area of cell profiles, nuclear-cytoplasmic ratio, and density of cytoplasmic secretory granules). Both pretreatment and post-treatment values in our patients with duodenal ulcer significantly differed from those of a previous investigation of healthy volunteers with regard to the volume density of enterochromaffin-like cells and non-granulated cells, which increased, and of D cells, which markedly decreased. The latter result may provide a cellular basis for impairment in the paracrine release of fundic somatostatin in peptic ulcer disease. Finally, morphometric data on endocrine cell volume density provided by electron microscopy were found to correlate with those obtained in the same patients using light microscopy techniques (Grimelius silver impregnation and chromogranin A immunostaining). It is concluded that 6 months' treatment with pharmacological doses of omeprazole is devoid of appreciable trophic effect on endocrine cells of human oxyntic mucosa.

Gastric carcinoids and their precursor lesions. A histologic and immunohistochemical study of 23 cases.

A histologic and immunohistochemical study was carried out in 23 unselected nonantral gastric carcinoids and their precursor lesions classified according to Solcia et al. None of the patients showed Zollinger-Ellison syndrome. Two variants of carcinoids showing distinctive pathologic and pathogenetic characteristics were identified on the basis of presence or absence of associated chronic atrophic gastritis type A (A-CAG). Chronic atrophic gastritis type A was found in 19 cases showing either single or multiple neoplasms, tumor extension limited to the mucosa or submucosa, consistent endocrine cell precursor changes in extratumoral mucosa, and consistent hypergastrinemia and/or G cell hyperplasia. Associated precursor lesions were only hyperplastic in all but two cases with single carcinoids whereas they were also dysplastic in all but one case with multiple carcinoids. The four tumors arising in nonatrophic mucosa were all single, more aggressive, and not associated with extratumoral endocrine cell proliferations or with signs of gastrin hypersecretion. Tumor cells were diffusely immunoreactive for chromogranin A and synaptophysin but usually negative for chromogranin B or HISL-19. Scattered serotonin cells were found in ten carcinoids. They were more frequent in infiltrating than in intramucosal tumors as were the less represented pancreatic polypeptide cells whereas the reverse was found for alpha-subunit-containing cells. These results are of relevance for tumor pathogenesis and may provide the rationale for a less aggressive therapeutic approach in the patients.

Quantitative ultrastructure of endocrine cells of oxyntic mucosa in Zollinger-Ellison syndrome. Correspondence with light microscopic findings.

The endocrine cells of the oxyntic mucosa of five patients with longstanding Zollinger-Ellison syndrome were quantitatively investigated with electron microscopy and two light microscopic methods (Grimelius and immunostaining for chromogranin A). Ultrastructurally, the volume density of endocrine cells was 3.2% +/- 1.1% of the mucosal epithelial component, a 168% increase (P less than 0.001) over the value found in normal subjects. Of the six endocrine cell types of human oxyntic mucosa, only enterochromaffinlike cells increased in cell density (65% +/- 15% of the total endocrine cell mass), size, and number of cell profiles per unit area. The enterochromaffinlike cells also underwent morphological changes of secretory granules with a decrease in vacuolated forms, increase in elongated profiles, and appearance of granules with a punctate structure of the core. The latter variety of granules was previously observed only in carcinoid tumors of the oxyntic mucosa and is possibly related to the enterochromaffinlike cell hyperplasia-neoplasia sequence seen in hypergastrinemic patients. A positive relationship was found between endocrine cell densities evaluated ultrastructurally and with chromogranin A immunostaining. It is concluded that in Zollinger-Ellison syndrome, the trophic effects induced by longstanding hypergastrinemia are strictly selective for enterochromaffinlike cells and are associated with ultrastructural features typical for enterochromaffinlike cell tumors.

Glycoprotein hormone alpha subunit in endocrine cells of human oxyntic mucosa. Studies on its relation to neuroendocrine tumors.

Expression of the alpha-subunit of glycoprotein hormones is an acquired feature of the endocrine cells of the oxyntic mucosa in patients with sustained serum levels of gastrin, and may be related to the hyperplasia-carcinoid sequence occurring in these patients. In the present study we have investigated the intragastric cellular localization and the circulating levels of alpha-subunit in a patient with Zollinger-Ellison syndrome. In this patient we have found that: 1) Endocrine cells accounted for 2.29% +/- 1.44% of the total oxyntic mucosal volume (normal value: 0.9% +/- 0.4%), with the ECL cells representing 63.22% +/- 10.9% of the total endocrine cell volume (normal value: 29.8 +/- 8.8%). 2) Cells immunoreactive for the alpha-subunit were found to correspond ultrastructurally to a subpopulation of enterochromaffin-like cells, indistinguishable from similar cells devoid of significant immuno-electron microscopic labeling. 3) Immunoreactive cells included a portion of oxyntic endocrine cells with punctate granules, a feature previously observed only in carcinoid tumors of the oxyntic mucosa. 4) In consecutive sections of freeze-dried vapor-fixed biopsies a fraction of alpha-subunit storing cells was found to co-express histamine. 5) The serum alpha-subunit levels were abnormally elevated and paralleled those of gastrin in a secretin-stimulation test. Analysis of similar curves in two other patients with Zollinger-Ellison syndrome, and five patients with hypergastrinemic atrophic gastritis, all presenting alpha-subunit containing oxyntic endocrine cells, showed significant alpha-subunit elevations only in the patients with ulcerogenic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

A new method of grading malignancy of prostate carcinoma using quantitative microscopic nuclear features.

A morphometrical assessment of nuclear features and a DNA study were performed on prostate tissue specimens from 33 patients with prostate carcinoma using an image analysing computer. Six nuclear geometric variables were measured and their mean, standard deviation (SD) and standard error (SE) were calculated for each case. The data on nuclear DNA content obtained by static cytometry were processed using an algorithm which provided a DNA grade of malignancy (DNA MG). Using the stepwise multiple regression, we found a significant correlation (p less than 0.01) between the DNA MG, chosen as the dependent variable in the statistical model, and the following nuclear features in decreasing order of importance: area SD, convex perimeter SE, and the mean of maximum diameter. From the correlation coefficients of the variables an equation was built up which provided a geometric nuclear grade of malignancy (GNMG) on a morphometrical basis more closely related to the clinical stage of the tumour (r = 0.75) than the visually assessed histological grade (r = 0.68) based on the Gleason score. This new method of grading malignancy allows an objective and quantitative evaluation to be made of the biological behaviour of the tumour, as measured by the patient's clinical stage.

Composite carcinoid-adenocarcinoma of the stomach associated with multiple gastric carcinoids and nonantral gastric atrophy.

A case of multiple gastric carcinoids and nonantral atrophic gastritis in which the larger tumor was a composite carcinoid-adenocarcinoma is presented. The two components of the composite tumor immunohistochemically showed clear-cut diverging functional differentiations although the available evidence supported a common histogenesis from the metaplastic intestinal epithelium of the gastric mucosa. The carcinoid tissue of the composite tumor, which showed "atypical" features, also differed from the other, pure carcinoids, in which the histologic appearance was "typical." Total gastrectomy performed 1 month after the original gastric resection with antrectomy disclosed regressive changes in the endocrine cell proliferations of the gastric stump consistent with the withdrawal of a stimulating effect of the antral gastrin.