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The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between gastric adenoma and adenocarcinoma.

We screened 30 gastric adenomas and 72 gastric adenocarcinomas for four genetic alterations (mutations of the K-ras, APC, and p53 genes and loss of heterozygosity at the DCC genetic locus) which are known to occur during colorectal tumourigenesis. We used polymerase chain reaction (PCR) single-strand conformation polymorphism analysis to detect mutations. Loss of heterozygosity (LOH) at the DCC locus was ascertained directly by performing PCR on the variable number of tandem repeats within the gene. Mutations of the K-ras gene were not detected in any gastric adenoma or carcinoma. APC mutations were detected in 20 per cent (6/30) of the adenomas but in only 1.4 per cent (1/72) of the carcinomas. In contrast, the p53 gene was frequently mutated in carcinomas (35 per cent; 25/72), but not in adenomas. LOH at the DCC locus was a frequent occurrence in carcinomas (58 per cent; 11/19 informative cases) but was infrequent in adenomas (14 per cent; 1/7). Alterations of the p53 and DCC genes occurred frequently both in differentiated and in undifferentiated gastric carcinomas. The considerable differences in the incidences of genetic alterations between gastric adenoma and carcinoma indicate that the sequential development of gastric carcinoma from adenoma is uncommon in gastric carcinogenesis.

Adenocarcinoma↗

Differences in PTH (1-84) release in response to ambient calcium concentrations of parathyroid adenoma fragments and dispersed parathyroid adenoma cells in culture.

In a previous study we observed that during perfusion of normal human parathyroid tissue, the release of PTH (1-84) was modulated by ambient extracellular calcium (Ca++) and lithium (Li+) concentrations in the media and preliminary studies indicated that this stimulus-response coupling was absent in human parathyroid adenoma fragments. The present study compares the responsiveness of parathyroid adenoma fragments and isolated parathyroid adenoma cells from the same adenoma and their response to Ca++ changes and Li+ presence in culture media. The data indicate that parathyroid adenoma tissue fragments fail to respond to ambient changes in Ca++ and Li+. In contrast, dispersed parathyroid cells preparations responded with a significant increase of PTH (1-84) release (50%) under the influence of low ambient calcium concentrations. Six of the dispersed cell preparations also responded with a 45% decrease in PTH release under the influence of a high Ca concentration in the medium. Isolated parathyroid cells obtained from the same adenoma's did not respond to the presence of Li++ in the medium. These data suggest tat human parathyroid adenoma tissue functions autonomously and is not sensitive to calcium regulation in the tissue configuration as opposed to the isolated cell suspensions. The nature of this difference remains elusive.

Adenoma↗

Discriminatory power of MRI for differentiation of adrenal non-adenomas vs adenomas evaluated by means of ROC analysis: can biopsy be obviated?

The purpose of our study was to evaluate the discriminatory power of MRI in high-field magnet (1.5 T) for differentiation of adrenal non-adenomas vs adenomas assessing the following parameters separately and in combination: mean diameter of adrenal mass; previously described and new ratios as well as index calculated from signal intensity (SI) on SE T2-weighted images, chemical shift imaging (CSI), and Gd-DTPA-enhanced dynamic studies. One hundred eight adrenal masses (36 non-hyperfunctioning adenomas, 27 pheochromocytomas, 23 aldosterone-secreting adenomas, 20 malignant masses and 2 cortisol-secreting adenomas) in 95 patients were evaluated with SE sequences, CSI and Gd-DTPA dynamic studies. Indices and ratios of SI for all examined MRI methods were calculated and examined retrospectively for significance of differences between the groups with calculation of sensitivity and specificity. Receiver operating characteristics (ROC) analysis of calculated parameters in combination was performed. The multifactorial analysis of all four parameters, including size of the tumor, T2(liver) index, CSI ratio reflecting lipid content in the tumor and Wo(max/last) ratio reflecting maximal washout of contrast agent from the tumor had 100 % sensitivity and 100 % specificity in characterization of adrenal non-adenoma. The best performance of combination of mean tumor diameter with single MRI SI parameter was achieved in combination with T2(liver) index for all adrenal masses (area under ROC 0.987) and CSI ratio for non-hyperfunctioning adrenal masses (area under ROC 0.991). Magnetic resonance imaging enables sensitive and specific diagnosis of adrenal non-adenoma.

Adenoma↗

Colorectal high-grade adenomas: incidence, localization and adenoma-adenocarcinoma ratio in a retrospective and comparative population-based study of 225 consecutive cases between 1988 and 1996.

Colorectal high-grade adenomas can be regarded as precancerous lesions. This study collected epidemiological data from a defined region (Luxembourg) that can serve as reference data for designing a national screening program for early colorectal cancer detection. Nine pathologists diagnosed and reviewed slides retrospectively from 288 new colorectal and anal in situ carcinomas from the period 1988-1996 (63 were excluded for various reasons). In all, 225 new colorectal high-grade adenomas were considered. There were 129 men (57%) and 96 women (42%), and 78% of patients were aged over 60 years. Over this period we found an increase in incidence of high-grade colorectal adenomas (11 cases in 1988, 40 cases in 1996) for both sexes. The overall incidence rate was 2.9 x 100,000 in 1988 and 9.6 x 100,000 in 1996. The average annual age-standardized incidence rate for this period was 3.7+/-0.5 (95% confidence interval); the cumulative rate (0-74 years) was 0.4%. Three-fourths of the adenomas were situated in the rectum (n=78, 35%) or sigmoid colon (n=92, 41%). Histological diagnosis was provided by 160 total polypectomy specimens (71%), 30 surgical resections (13.3%), and 35 biopsy specimens (16%). Over the study period there was an increased incidence of new colorectal adenocarcinomas. There were eight times as many adenocarcinomas (n=1782) as adenomas (n=225); the distribution of anatomical sites was comparable. These epidemiological data on 225 new colorectal high-grade adenomas can be the basis for quality assurance in clinical and histological diagnostic procedures, especially in regard to the 1:8 ratio between high-grade adenomas and invasive adenocarcinomas and may provide additional data for the design of a regional or national colorectal cancer screening program.

Adenocarcinoma↗

Presence of high-level DNA copy number gains in gastric carcinoma and severely dysplastic adenomas but not in moderately dysplastic adenomas.

Our aim was to investigate the presence of DNA copy number changes in gastric adenomas and to identify the changes that may play a role in gastric carcinogenesis. DNA copy number changes in 16 patients with gastric adenoma and in 22 tumors from patients with intestinal type gastric carcinomas were studied by using comparative genomic hybridization. DNA copy number changes were found in 44% of the adenoma cases and in 86% of the intestinal type gastric carcinomas. On average, gains were more common than losses (0.9 vs. 0.5 in adenomas and 4.1 vs. 1.8 in carcinomas). In adenomas, the most common gains involved chromosome 8 in 3 cases, and gain of chromosome 7 and 20q was detected in 2 cases. The most frequent losses were observed at 5q (three times). Only adenomas with severe dysplasia showed high-level amplifications that were detected at chromosome 13, 17cen-q22, and 20q12-ter. In gastric cancer, the most common gains were detected at 20q (55%), 17q12-q21 (41%), and 8q (41%), and the most common losses were detected at 18q (41%) and 4q (32%). High-level amplifications were observed at 20q (3 tumors), 17cen-q21 (3 tumors), 2p (1 tumor), and 18q (1 tumor). These findings suggest that the progression of dysplasia is associated with higher levels of DNA copy number increase (e.g., the gains at 17q and 20q), which were typically observed in the intestinal type gastric cancer. Furthermore, the results support the hypothesis that adenoma precedes cancer.

Adenocarcinoma↗

Immunohistochemical analysis of pericryptal fibroblast sheath and proliferating epithelial cells in human colorectal adenomas and carcinomas with adenoma components.

In order to examine stromal-epithelial interaction during the oncogenic progression of large bowel tumors, the association between pericryptal fibroblast sheath (PCFS) and expression of Ki-67 antigen was evaluated in 87 cases of colorectal adenoma and 95 cases of carcinoma with an adenoma component (CWA). For the immunohistochemistry, anti-alpha-smooth muscle actin antibody (alpha-SMA) and anti-Ki-67 antigen antibody (MIB-1) were used. In adenomas and adenoma components of CWA, the quantity of neoplastic glands with PCFS was reduced relative to the progression of histological atypia. Pericryptal fibroblast sheath was virtually absent from invasive carcinoma areas of CWA. Increased expression of Ki-67 correlated with the degree of histological atypia of adenomas. A significant reverse correlation was also seen between Ki-67 expression and PCFS-positive glands in adenoma components of CWA. These findings suggest that the prevalence of PCFS and Ki-67 expression are important indicators of colorectal neoplasia progression. The significant reduction of PCFS in colorectal epithelial neoplasms reflects progression in the adenoma-carcinoma sequence.

Actins↗

Malignant transformation of adenoma in large intestine--especially on villous adenoma.

The incidence of 454 resected adenomas was histologically 87.8% of tubular, 7.7% of tubulovillous and 4.5% of villous adenomas, respectively. Eigtosigmoid region. Male to female ratio was 1 to 1.8, 1.5 to 1 and 1.8 to 1 for the villious, tubulovillous and tubular adenomas, respectively. Adenocarcinomas of large intestine consisted of 684 cases, 709 lesions and male to female ratio was 1 to 1.01. It should be considered that the adenomas in female may grow largely compared with those in male, with subsequent malignant transformation. Although the adenomas were found at the rate of 26.4% in the rectosigmoid region, 74.2% of the adenocarcinomas were found in this region, because the adenomas in this region grow largely compared with the other regions. Mucinous carcinomas were found in 33%, 23% and 9%, respectively, in the adenocarcinomas with remaining adenoma showing villous, tuvulovillous and tubular types.

Adenocarcinoma↗

Pituitary adenomas in acromegalic patients: an immunohistochemical and endocrinological study with special reference to prolactin-secreting adenoma.

To establish a functional classification of purification of pituitary adenomas in acromegalic patients, we used immunoperoxidase-staining techniques specific for GH and PRL. Surgical specimens from 55 acromegalic patients were studied. GH was demonstrated in all adenomas and PRL was found in 25 of them (45.5%). Immunohistologically, GH- and PRL-containing adenomas could be divided into 3 types. In type 1 (11 patients), immunoreactive PRL was present in single cells surrounded by immunoreactive GH cells. In type 2 (6 patients), immunoreactive PRL cells formed clusters. In Type 3 (8 patients), immunoreactive PRL and GH cells demonstrated a mosaic pattern, and it was difficult to determine which were in the majority. A double immunostaining method revealed 15 adenomas in which individual cells contained both GH and PRL. Hyperprolactinemia was present in 21 patients, 15 of these had immunoreactive PRL cells (type 1, 4 patients; type 2, 3 patients; type 3, 8 patients). There was no correlation between the size of the adenoma and its type. Endocrinologically, all patients with type 2 and 3 adenomas had an abnormal serum GH response to TRH administration; all type 3 patients had a substantial serum PRL response to TRH administration. Type 3 is considered to be an actively PRL-secreting adenoma, resulting in hyperprolactinemia.

Acromegaly↗

Identification of gonadotroph adenomas in men with clinically nonfunctioning adenomas by the luteinizing hormone beta subunit response to thyrotropin-releasing hormone.

Because of the recent finding that a majority of clinically nonfunctioning pituitary macroadenomas in women could be identified as of gonadotroph origin by their LH beta-subunit responses to TRH, we evaluated in this study the value of the LH beta-subunit response to TRH in identifying gonadotroph adenomas in men with clinically nonfunctioning macroadenomas. Thirty-eight consecutively studied men with clinically nonfunctioning macroadenomas were given TRH iv, and intact FSH and LH and LH beta- and alpha-subunits were measured every 15 min for 90 min before and 90 min after. TRH tests were also performed on 15 healthy, age-matched control men and on 12 men with adenomas secreting GH or PRL. Of the 38 men with clinically nonfunctioning macroadenomas, basal values were supranormal in 10 for FSH and in 6 each for alpha- and LH beta-subunits. Responses to TRH were elevated, compared to the healthy, age-matched controls, in 14 for LH beta-subunit and in 5 each for intact FSH and LH. None of the men with adenomas secreting GH or PRL exhibited supranormal responses to TRH. Of the 38 clinically nonfunctioning adenomas, 35 were established in dispersed cell culture, and 29 secreted readily detectable amounts of intact FSH, LH, and LH beta-subunit, strongly suggesting that these adenomas were of gonadotroph cell origin. We conclude that the LH beta-subunit response to TRH can identify gonadotroph adenomas in men with clinically nonfunctioning adenomas better than can basal concentrations of intact FSH and alpha-subunit, alone or combined, but not as well as it can in women.

Adenoma↗

[Should silent corticotroph-cell adenoma be classified as a non-functional pituitary adenoma?].

A 45-year-old man underwent surgery for a silent corticotroph-cell pituitary adenoma which developed in 9 months. The tumor was termed silent because it exhibited increased corticotropic secretion without clinical signs of hypercorticism. This classes it as a non-functional adenoma. The non-functional group includes different types of adenomas such as gonadotroph and other silent thyreotroph and somatotroph adenomas with variable proliferative potential. Silent corticotroph-cell adenoma is considered as an aggressive tumor. In contrast, gonadotroph adenomas usually grow slowly and postoperative tumor remnants can remain stable for years. Because of this variability in tumor growth, the therapeutic decision is difficult if there is a postoperative remnant. No precise guidelines can be established. We suggest that non-functional pituitary adenomas should be considered separately, according to the histological type. This classification is essential for improving knowledge and specifying indications for radiotherapy.

Adenoma↗

Colorectal counterpart of gastric depressed adenoma. A comparison with flat and polypoid adenomas with special reference to the development of pericryptal fibroblasts.

The histological features of 28 depressed adenomas (DAs) were compared with those of 40 flat adenomas (FAs) without a central depression and those of 29 polypoid adenomas (PAs), with special reference to the development of pericryptal fibroblasts (PCFs), using immunohistochemical staining for muscle-specific actin (HHF-35). The DAs were composed of a crowded collection of adenomatous tubules with smaller diameters than those of the PAs. With regard to PCF development, the DAs had poorly developed PCFs; PCF (-), (+), and (++) numbered 12 (43%), 16 (57%), and 0 (0%), respectively. On the other hand, the nondepressed adenomas (PAs and FAs) had well-developed PCF; PCF (-), (+), and (++) numbered 5 (7%), 35 (51%), and 29 (42%), respectively. In addition, the number of PCFs seemed to decrease in the sequence of PAs, followed by FAs and DAs. According to our results, the DAs had a characteristic histological architecture together with poorly developed PCFs features, which distinguished them from the PAs. In conclusion, the depressed adenomas were considered a subtype of the flat adenomas. The depletion of PCFs seems to correlate with the depressed growth of the adenoma.

Actins↗

Effects of growth hormone-releasing hormone (GHRH) on densely granulated somatotroph adenomas and sparsely granulated somatotroph adenomas in vitro: a morphological and functional investigation.

The effects of growth hormone-releasing hormone (GHRH) were studied on densely granulated somatotroph adenoma cells and sparsely granulated somatotroph adenoma cells in culture by measuring release of growth hormone (GH) as well as ultrastructural morphometrical parameters and comparing them with those of control adenoma cells. Both types of adenoma cells cultured with GHRH showed similar increases of GH release into culture media and exhibited similar increases in cytoplasmic volume densities (CVD) of endoplasmic reticulum and Golgi apparatus and decreases in CVD of secretory granules and secretory granule diameter. These results indicate that (1) both types of somatotroph adenoma cells react similarly to GHRH stimulation, despite their morphologic differences, and (2) GHRH stimulates GH synthesis as well as GH release by somatotroph adenoma cells.

Acromegaly↗

Comparison of cyclo-oxygenase 2 expression in colorectal serrated adenomas to expression in tubular adenomas and hyperplastic polyps.

BACKGROUND AND AIMS: Serrated adenoma (SA) is a newly defined category of colorectal neoplasia that contains features of both adenoma and hyperplastic polyp, and has two patterns, hyperplastic and cerebriform patterns. Since cyclooxygenase 2 (COX-2) has been found upregulated in colorectal cancers and adenomas, we examined whether either the hyperplastic or cerebriform pattern of SA has the potential for tumor progression and should be a target for clinical treatment. PATIENTS AND METHODS: An immunohistochemical scoring system was used to compare COX-2 expression in colorectal SAs (n=79), tubular adenomas (n=66), and hyperplastic polyps (n=21). RESULTS: COX-2 scores were significantly higher in SA of the cerebriform pattern (n=44) than in SA of the hyperplastic pattern (n=35). There was no difference in COX-2 scores between SA of the cerebriform pattern and tubular adenoma. In SA accompanied by hyperplastic polyp (n=26) the hyperplastic components expressed little COX-2, the same as traditional hyperplastic polyps. COX-2 expression in the SA component was similar to that in pure SA. CONCLUSION: SA of the cerebriform pattern should be treated similarly as traditional tubular adenomas. COX-2 induction may additionally be involved in progression from hyperplastic polyp to SA.

Adenoma↗

Canalicular adenoma: not a basal cell adenoma.

The evidence that canalicular adenomas and basal cell adenomas are separate entities is presented in this article. The clinical features were studied in a series of 13 previously unreported salivary gland tumors (5 canalicular adenomas and 8 basal cell adenomas) and 99 examples derived from the literature (68 canalicular adenomas and 31 basal cell adenomas). Representative tumors from the new cases and from 66 referred cases were studied by histologic, histochemical, and electron microscopic techniques. The two tumors differ significantly with respect to the age range of affected patients, site of predilection, and morphologic and histochemical features.

Adenoma↗

Histologic localization of PLAG1 (pleomorphic adenoma gene 1) in pleomorphic adenoma of the salivary gland: cytogenetic evidence of common origin of phenotypically diverse cells.

Pleomorphic adenoma gene 1 (PLAG1), a zinc finger transcription factor gene, is consistently rearranged and overexpressed in human pleomorphic adenomas of the salivary glands with 8q12 translocations. In this report, we describe the immunohistochemical localization of PLAG1 protein in pleomorphic adenomas of the salivary gland and corresponding normal tissue, in relation to cytokeratin, vimentin, and BCL-2 expression. Normal salivary gland tissue was not immunoreactive for PLAG1. In primary pleomorphic adenomas, cells strongly immunoreactive for PLAG1 were detected in the outer layer of tubulo-ductal structures, which are thought to be the origin of cells with bi-directional, epithelial, and mesenchymal phenotypes. In contrast, epithelial cells with abundant cytokeratin in the inner tubulo-ductal structures only sporadically expressed PLAG1. BCL-2 immunoreactivity was found mainly in the cells surrounding the tubulo-ductal structures and in the solid undifferentiated cellular masses, within the areas that had moderate PLAG1 immunoreactivity. The variability of PLAG1 expression in neoplastic cells seemed to reflect the morphologic heterogeneity that correlated with the stage of differentiation of the tumor cells. Immunohistochemical/cytogenetic evaluation of two pleomorphic adenomas with t(3;8)(p21;q12) or t(5;8)(p13;q12) translocations demonstrated the clonal nature of immunophenotypically diverse cells. This finding confirms the theory that pleomorphic adenoma cells share a common single-cell origin, most likely from the epithelial progenitor basal duct cells.

Adenoma, Pleomorphic↗

The effects of age and spontaneous adenoma formation on trophic activity in the rat pituitary gland: a comparison with trophic activity in the human pituitary and in human pituitary adenomas.

The effects of ageing on trophic activity in the pituitary gland and the molecular events that underlie pituitary tumour formation are poorly understood. In the present study we have used an extremely accurate system to analyse trophic activity in human pituitary tumours and compared our findings with trophic activity in spontaneous rat pituitary adenomas and with changes in basal rates of turnover as the animals age. Thin, hematoxylin and eosin-stained pituitary sections from groups of male Wistar rats aged 6 weeks to 16 months, killed at 90-min intervals after receiving a single intraperitoneal bolus of colchicine to block cellular passage through mitosis, were evaluated histologically. Extremely accurate quantification of small changes in the prevalence of trophic events, and thus the rate of cell turnover, was achieved using a dedicated computerized aid to manual cell counting. Results were compared with the prevalence of mitotic activity in 24 spontaneous rat pituitary adenomas and with a series of 97 archival human pituitary adenomas and 24 normal human pituitary glands obtained at autopsy. In rats, average basal pituitary cell turnover declined by over 95% between 6 weeks and 16 months of age. Concurrent with this decline was a marked increase in the prevalence of adenoma formation. The prevalence of mitotic activity in spontaneous rat pituitary adenomas averaged almost twice that seen in normal, young rat pituitary and exceeded 16 times that seen in the pituitary of aged animals. In contrast, when compared to normal human pituitary tissue, average trophic activity in human pituitary adenomas remained extremely low.

Adenoma↗

Is the adenoma-carcinoma sequence contradicted by the differing location of colorectal adenomas and carcinomas?

This article takes a look at the different localisation of colorectal adenomas and carcinomas. The risk of malignancy of 4,257 adenomas found in 1742 patients was determined, and the lesions grouped in accordance with various criteria and risk classes. It was found that the distribution of adenoma locations approximated all the more closely to the distribution pattern of carcinoma sites, the higher the malignancy risk of an adenoma group was. The statistical approximation of adenoma and carcinoma localisations as a function of increasing risk of malignancy must be considered an argument in support of the adenoma--carcinoma sequence.

Adenoma↗

The adenoma-carcinoma sequence in rectal adenomas. Support by the expression of blood group substances and carcinoma antigens.

The reaction patterns of eight antibodies directed against blood group substances A, B, and H and against Lewis B antigen, difucosylated carbohydrate antigens (DFCA), gastrointestinal cancer antigen (GICA) CA 19-9, carcinoma-associated antigen CA-50, and carcinoembryonic antigen (CEA) were studied in mucosa and adenomas of the rectum. Antigenic heterogeneity was a common feature of rectal mucosa and was observed to a considerable degree in adenomas. In general, the rectal mucosa expressed only a few antigens and to a limited extent. The adenomas were more extensively stained than the rectal mucosa. The proportion of positive cells increased with the grade of dysplasia but was relatively unrelated to the histologic type. The proportion of individual antigens expressed and the number of antigens extensively expressed increased between rectal mucosa, benign adenomas, and adenomas with early invasive carcinoma. These findings support the concept of an adenoma (dysplasia)-carcinoma sequence.

ABO Blood-Group System↗