[Interdisciplinary guidelines for diagnosis and therapy of extracerebral amyloidosis: issued by the German Society of Amyloid Diseases e. V. (www.amyloid.de)].
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Amyloid↗
Biomedical subjects
Wolfgang Saeger
Publications and source records attributed to Wolfgang Saeger.
Low prevalence of Gs alpha mutations in śomatotroph adenomas of children and adolescents.
Mutations in the gene coding for the alpha-subunit of the heterotrimeric stimulatory G protein Gs are the most frequently identified molecular events in the development of somatotroph adenomas in adults. In children and adolescents, somatotroph adenomas are rare, and only two cases with the Gs alpha mutation have been reported so far. In this study, we therefore investigated the prevalence of activating Gs alpha mutations in 17 patients younger than 20 years with pituitary growth hormone-secreting adenomas and examined the characteristics of mutation-positive cases. The most common C-->T substitution in codon 201 was detected in two children. Interestingly, in contrast to the remaining cases, the adenomas positive for the Gs alpha mutation proved to be nonsporadic, but part of a syndrome associated with endocrine tumors in both individuals. Additional tests confirmed McCune-Albright syndrome in the first patient and multiple endocrine neoplasia type 1 syndrome in the second patient. In contrast to the findings in adult cases, somatotroph adenomas in young patients seem to carry somatic Gs alpha mutations at a lower frequency, and germ-line or early postzygotic mutational events may be responsible for the shortened latency of tumorigenesis.
Adolescent↗
Nuclear beta-catenin accumulation as reliable marker for the differentiation between cystic craniopharyngiomas and rathke cleft cysts: a clinico-pathologic approach.
Clinical and histopathologic differentiation of cystic lesions from the sellar region, that is, craniopharyngiomas (CPs) and Rathke cleft cysts (RCCs), is challenging and has paramount importance with respect to variable clinical manifestation and adapted surgical treatment strategies in both entities. Here, we retrospectively evaluated clinico-pathologic findings in 81 patients presenting with a cystic tumor located in the sellar region. All patients underwent transsphenoidal or transcranial resections. Microscopic inspection of surgical specimens identified CP in 51 patients, and RCC in 30 patients. Amongst the panel of immunohistochemical marker proteins used for histopathologic analysis, nuclear accumulation of beta-catenin was detectable only in CP. On the basis of the histopathologic and immunohistochemical analysis, clinical presentation (sex, age, ophthalmologic, and endocrinologic deficits), imaging (tumor location, size, and calcification), as well as a description of cyst contents obtained during operation were retrospectively evaluated. In purely cystic CPs, an isointense signal was more frequent in T1-weighted magnetic resonance images and calcification of the tumor capsule in computed tomography scans. In addition, the size of RCC was smaller and this tumor entity was more often located within the sella. Aberrant (nuclear) immunohistochemical staining for beta-catenin appeared, however, as most reliable factor for the differentiation between purely cystic CPs and RCCs, whereas tumor location, tumor size, and calcification of the tumor capsule were less consistent parameters. The data are compatible with distinct pathogenic pathways associated with these related histopathologic entities.
Adolescent↗
Expression of connexins in chromaffin cells of normal human adrenals and in benign and malignant pheochromocytomas.
Decrease in connexin (Cx) expression and loss of gap junctional intercellular communication (GJIC) have been associated with aberrant cell growth and enhanced neoplastic phenotype. We studied the expression of Cx26, Cx32, Cx43, and Cx50 in chromaffin cells of 10 normal human adrenal glands, 10 benign, and 13 malignant pheochromocytomas. Immunohistochemistry showed that Cx50 expression seemed to be the predominant form of Cx expressed in human chromaffin cells, whereas Cx43 immunoreactivity was the most prominent form found in the adrenal cortex. However, Western blotting revealed that nonphosphorylated and singly and doubly phosphorylated forms of Cx43 were present within the malignant adrenomedullary cells at the same time. Cx26 and Cx32 were distributed inhomogeneously with no emphasis of expression in the types of tissues studied. Cx50 expression was diminished in malignant pheochromocytomas. We conclude that there is a differential expression of Cx in human adrenals. Immunohistological testing for Cx expression does not however allow differentiation of benign from malignant pheochromocytomas.
Adrenal Gland Neoplasms↗
Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data.
OBJECTIVE: The aim of this study was to examine pituitary adenomas in a series of postmortem pituitaries by use of modern technologies of immunostaining, to classify the adenomas according to the current WHO classification and to analyse the possible associations to the available clinical data. METHODS: In this study, pituitaries of 3048 autopsy cases obtained from autopsy series of the years 1991-2004 were examined. RESULTS: A total of 334 pituitary adenomas were found in 316 pituitaries. One hundred and thirty-two sparsely granulated prolactin cell adenomas (39.5%), 75 null cell adenomas (22.5%) and 31 oncocytomas were diagnosed. Forty-six ACTH cell adenomas (13.8%, 27 densely granulated, 19 sparsely granulated) and one adenoma composed of Crooke's cells were detected. Twenty-two gonadotroph cell adenomas (6.6%), seven GH cell adenomas (four sparsely granulated, three densely granulated), one mixed GH cell-PRL cell adenoma, two TSH cell adenomas, five plurihormonal adenoma type I, four plurihormonal adenoma type II and two alpha-subunit-only adenomas were seen. Six adenomas remained unclassified because the tissue was not contained in all sections for immunohistochemistry. Seventeen pituitaries included multiple tumours. The overall tumour size ranged from 0.1 to 20 mm in diameter. Among 76 adenomas (22.7%), which had a tumour size of > or = 3 mm, only three tumours were macroadenomas corresponding to a tumour size of more than 10 mm. The evaluation of the available clinical data showed 99 cases of hypertension, 65 cases of diabetes mellitus, six patients with hyperthyroidism and four with hypothyroidism. No symptoms of adenohypophyseal hormone hypersecretion were reported. The statistical correlations to clinical data were discussed. CONCLUSIONS: Adenomas in postmortem pituitaries differ from those in surgical series in proportion of adenoma types and biological behaviour.
ACTH-Secreting Pituitary Adenoma↗
Comment to the 2004 World Health Organization classification of pituitary tumors.
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Cyclin D1↗
Advanced glycation end products in intervertebral discs and hip joint capsules: correlation with senile amyloid?
Advanced glycation end-products (AGEs) may be involved in either amyloidogenesis or complications related to amyloid. The incidence of AGE increases with age as does the prevalence of amyloid affecting the hip joint capsule and intervertebral discs. We hypothesized that AGEs may be involved in the pathology of these amyloidoses and investigated the spatial and temporal relationship between AGEs and amyloid of intervertebral discs and hip joint capsules. Using immunohistochemistry, AGEs were found in all 71 intervertebral discs and all 87 hip joint capsules. Amyloid was present in 59 (83%) intervertebral discs and 65 (75%) hip joint capsules. AGEs were found in the immediate vicinity of amyloid deposits in 104 of 253 (41%) investigated amyloid deposits of the intervertebral discs and 159 of 311 (51%) investigated amyloid deposits of the hip joint capsules. However, only rarely were AGEs demonstrated within amyloid deposits. No linear correlation was found between the amount of AGEs and the amount of amyloid deposited. As AGEs are more common than amyloid in intervertebral discs and hip joint capsules, it is conceivable to suggest that AGEs might be involved in the pathogenesis of amyloid at these anatomical sites. However, the amyloid proteins appear not to be modified and AGE modification is not a general characteristic of senile amyloidoses.
Adult↗
Pituitary tumors: prognostic indicators.
Many factors influence the proliferation of pituitary adenomas: angiogenesis, apoptosis, growth factors, oncogenes, tumor suppressor genes, and hormone receptors. These elements can be demonstrated by immunohistochemistry and/or molecular pathology but no single factor can be used for determination of biological behavior resp. prognosis. Pituitary adenomas can be enclosed or invasive and may be very large or may be microadenomas, but the most important point for prognosis is the total resection in the first or second surgery or the reaction on treatments by drugs. Especially for residual tumor tissue proliferation, markers are important because they may indicate the growth rate and the aggressiveness of the tumor. Radiation therapy is indicated in many of these recurrent tumors and can improve the prognosis.
Adenoma↗
Proliferation markers and cell cycle inhibitors in pituitary adenomas.
Proliferation markers are widely used in general surgical pathology and also in pituitary pathology. They should help for differing aggressive or rapidly growing tumors from those with slower growth, as cellular atypia is not helpful for identifying aggressive adenomas of the pituitary. Only the number of mitoses is important for prognosis. A lot of markers can be used: antibodies for cyclins A, B, D and E, for proliferating cell nuclear antigen, Ki-67/Mib-1, antibodies for the inhibitory proteins p16, p27, p53, and for DNA topoisomerase IIalpha. A marker for apoptosis and its inhibitors may be also important. From our experiences, Mib-1 is the most reliable marker. The recommendation of this marker in the WHO classification of pituitary adenomas is fully justified.
Adenoma↗
Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue.
Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P<0.05). Nonsecreting adenomas exhibited a stronger tendency towards overexpression of uPA in invasive tumours when compared to noninvasive adenomas (Chi-square P=0.053). We found no correlation of MMP-9 expression and tumour invasion. TIMP-2 was overexpressed in noninvasive as compared to invasive adenomas (Chi-square P<0.05). The interrelationship between MMPs and serine proteinases in pituitary adenomas remains to be elucidated. From our data, a correlation between IL-6 and an activation of MMP-9 cannot be proven. The uPA-system may, however, play a role in dural invasion of pituitary adenomas.
Adenoma↗
TSPY-LTA transgenic mice develop endocrine tumors of the pituitary and adrenal gland.
In an attempt to determine the susceptibility of spermatogonia to malignant transformation transgenic mice were generated harboring a 1.3 kb 5'-flanking region of the germ cell specific expressed human testis specific protein, Y-encoded gene fused with the simian virus 40 large T antigen (TAg). Unexpectedly, TAg expression in transgenic mice was also detected in somatic tissues. Between days 65 and 85 after birth most of the transgenic mice developed anterior lobe tumors of the pituitary gland and to a less extent medulla type tumors of the adrenal gland. In addition, a few older transgenic mice developed tumors of the seminal vesicle, but no testicular tumors were observed in transgenic mice up to an age of 5 months. The pituitary tumors were immunoreactive for anti-prolactin (PRL) and anti-adrenocorticotropic hormone (ACTH). PRL and corticosterone concentrations in serum of transgenic mice were significantly increased. Taken together, our studies provide a novel mouse model for pituitary adenomas displaying a unique combination of hormone expression by tumor cells secreting PRL and ACTH.
Adrenal Gland Neoplasms↗
Advanced glycation end products and receptor for advanced glycation end products in AA amyloidosis.
Advanced glycation end products (AGEs) may be involved in either amyloidogenesis or complications related to amyloid. We hypothesized that AGEs may influence the pathogenesis of AA amyloidosis, and investigated the spatial and temporal relationship between AGEs, carboxy methyl lysine (CML), the AGE receptor (RAGE), and AA amyloid in humans and mice. Specimens from patients with AL and ATTR amyloidosis served as a control. Using immunohistochemistry, AGEs, CML, and RAGE were found within amyloid deposits, more commonly in AA amyloid than in AL amyloid and not in ATTR amyloid. Western blotting showed that multiple proteins (between 12 and >60 kd) are modified, but not the AA amyloid fibril protein itself. In the murine model of AA amyloidosis, we found a marked interindividual variability with respect to local and systemic CML levels, as well as to splenic RAGE transcription. Serum levels of CML correlated with the duration of the inflammatory response but not with amounts of splenic RAGE mRNA. Other as yet unidentified variables, especially of the heterogeneous group of AGEs, probably modulate transcription of RAGE and influence amyloidogenesis. CML serum levels, in turn, may prove useful in predicting patients at risk.
Adult↗
Hormone markers in pituitary adenomas: changes within last decade resulting from improved method.
The significance of polyclonal antibodies for demonstration of hormone expression in pituitary adenomas was compared with the significance of monoclonal antibodies (MAbs). Adenomas were classified by light microscopic structures in paraffin- and epon-embedded sections, by immunostaining for all pituitary hormones, and in part by electron microscopy. In the first series, 166 adenomas were studied with polyclonal antibodies during 1990 and 1991. In the second series, 572 adenomas were immunostained with MAbs during 1999 and 2000. In the first series, a very typical type-specific hormone expression was demonstrable in 63.2% of adenomas in contrast to 91.1% in the second series. Consequently, in the first series 36.7% of adenomas expressed additional or atypical hormones in >10% of adenoma cells, whereas in the second series only 8.9% contained additional hormones. We conclude that MAbs show a clearer cutoff in immunostainings of pituitary hormones and therefore should be preferred for adenoma classification.
Adenoma↗
Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
BACKGROUND: Structural changes, like atrial fibrosis, may increase the likelihood of atrial fibrillation (AF) occurring in response to triggering events. The influence of isolated atrial amyloidosis (IAA) is largely unknown. METHODS AND RESULTS: Right atrial appendages (1 or 2 entire cross sections) were obtained from 245 patients undergoing open-heart surgery. Atrial amyloid was identified by Congo red staining and classified by immunohistochemistry. Amyloid was found in 40 (16.3%) of 245 patients, and all deposits were immunoreactive for atrial natriuretic peptide (ANP). Thirty-eight (15.5%) patients suffered from persistent AF. The presence of amyloid correlated with age and P-wave duration and was related to sex, valve diseases, and the presence of AF (P<0.01). The association between atrial amyloid, AF, and P-wave duration was independent of age and sex. According to multiple logistic regression analysis, amyloid was the only age- and sex-independent predictor for the presence of AF. Atrial fibrosis was not a predictor for AF, and the amount of amyloid correlated inversely with the degree of interstitial fibrosis (P=0.001; r=-0.55). CONCLUSIONS: Our study provides evidence that IAA affects atrial conduction and increases the risk of AF. The occurrence of IAA depends on age leading to the formation of an amyloid nidus. The progression and consequences of IAA are then influenced by pathological conditions, such as valve diseases, that increase synthesis and secretion of ANP. The inverse correlation between IAA and atrial fibrosis suggests that these patients may not benefit from treatment with ACE inhibitors to reduce the amount of atrial fibrosis.
Adult↗
Intrasellar gangliocytomas associated with acromegaly.
The present study was designed to investigate the immunohistochemical characteristics of gangliocytomas associated with growth hormone (GH)-secreting pituitary adenomas. In our surgical collection of 476 GH-secreting adenoma cases, we examined tumor tissue from 6 patients (1.3%). All 6 patients were women, ranging from 29 to 52 years (mean, 40.3 +/- 9.5 SD) of age. Among 470 patients with GH-secreting adenomas without gangliocytoma, there were 255 female and 215 male patients. The preponderance of female patients with gangliocytomas was striking. Histological examination of the resected specimens showed areas of ganglion cells and adenomatous cells. Ganglion cell lesions were stained positively for synaptophysin (4 of 4; 100%) and neurofilament (4 of 4; 100%) as well as GH-releasing hormone (5 of 6; 83.3%). Subtypes of GH cell adenomas included 4 cases of sparsely granulated type and 2 cases of mixed GH and prolactin (PRL) cell adenomas. Based on these findings, we hypothesized that the intrasellar gangliocytoma promoted the growth of the pituitary adenoma by chronic overstimulation from excess GH-releasing hormone.
Acromegaly↗
Expression of Growth Factors in Normal and Neoplastic Pituitary Tissues.
Many growth factors are expressed in normal pituitary cells and pituitary tumors. They are involved in gene expression for pituitary hormones and in cell proliferation. Some appear to be important for prognosis or treatment. Strong overexpression of some growth factors may indicate a more rapid growth. The significance of the different growth factors for pituitary function and pathology is discussed.
Journal Article↗
Lymphocytic Hypophysitis: Light and Electron Microscopic Findings and Correlation to Clinical Appearance.
Light and electron microscopic findings of six cases of lymphocytic hypophysitis of a collective of 2500 surgical specimens are presented. Five cases were obtained by surgery, one case was obtained from autopsy. Light microscopy revealed an infiltration of mature lymphocytes and plasma cells in the interstitium, partly in the acini, as well as in the posterior lobe and the capsule. The structure of the remaining anterior lobe was normal. The final stage of lymphocytic hypophysitis is fibrosis, which was seen in all cases to varying degrees. The infiltrate consisted mainly of Tiymphocytes, being positive for CK 45 RO and CD 43. Immunocytochemical staining revealed different proportions of residual adenohypophyseal cells. Mainly prolactin reactive cells were observed as were growth hormone reactive cells. By electron microscopy some ruptured acini and damaged adenohypophyseal cells could be seen. Few pituitary cells contained enlarged lysosomal bodies or oncocytic changes. lnflammation causing enlargement of the pituitary leads to patients often being operated under the preoperative diagnosis of a tumor of the sellar region. It is important to identify this special type of hypophysitis, as a different course of treatment is required.
Journal Article↗
Hyperplastic and Tumorous Lesions of the Adrenals in an Unselected Autopsy Series.
In an unselected consecutive postmortem series, 512% of the adrenals showed cortical nodules with diameters up to 1 mm in 13%, between 1 and 2 mm in 28% and < 2 mm in 12%. In 22% of cases only one nodule was present; whereas in 15% two nodules and in 17% more than three nodules were found. A cortical adenoma was detected in 5% of cases. Adenomas were smaller than 6 mm in 1% and < 15 mm also in 1% of the entire collection. For differentiation of nodules criteria listed in Table 4 were used. Correlation with clinical data revealed a significantly higher number of nodules and an adenoma more frequently in hypertensive patients. Metastases were found in 19% of all cases with malignant tumors. Twenty-three percent of the metastases were smaller than 1 mm and 20% were < 10 mm in diameter. Adrenal metastases usually indicated generalized dissemination of the tumor.
Journal Article↗