Search

This study provides a base for evaluating incidentalomas. The incidence and type of pathological findings in a large group of surgically removed adrenal glands were analyzed: 282 resected adrenals from the years 1995 to 2004 were examined; 242 adrenals were removed for therapy of renal cell carcinomas (in one case both adrenals were removed). Other indications for adrenalectomies were malignant tumors (urothelial carcinoma, squamous cell carcinoma, sarcoma, lymphoma, etc.) and benign findings (oncocytoma, angiomyolipoma, pyelonephritis, etc.). A total of 18 adrenals exhibited a metastasis or diffuse infiltration of the adrenal or para-adrenal tissue by a malignant tumor (17 renal cell carcinomas, 1 non-Hodgkin's lymphoma). Seven adrenals exhibited an adenoma. Eighty-nine adrenal hyperplasias were diagnosed. Eighty-six adrenals included myelolipomatous or lipomatous foci. One hundred and thirteen adrenals (40.1%) did not exhibit any pathological findings. The adrenals exhibited infiltration or metastasis by malignant tumors (6.4%), adrenal adenomas (2.5%), adrenal hyperplasias (31.6%), and other alterations (38.7%).

A case of a 70-year-old man presenting with exsudative enteropathy due to light-chain-associated amyloidosis is reported. The diagnosis of systemic mastocytosis associated with IgG/lambda plasma cell myeloma and secondary generalised amyloidosis was carried out by morphological evaluation of bone marrow biopsy. The c-kit point mutation D816Y was detected by molecular analysis. Two years before, a cystadenolymphoma of the left parotid gland had been removed. A moderate increase of loosely scattered spindle-shaped mast cells, a subpopulation of them expressing CD25, an antigen that is not expressed by normal or reactive mast cells, was shown by retrospective analysis carried out on an intraparotideal lymph node. The c-kit mutation D816Y was shown by the molecular analysis of the lymph node. In summary, the notion that systemic mastocytosis may very rarely be associated with B cell neoplasms and that neoplastic mast cell infiltrates may be obscured because of only a minimal increase of atypical mast cells, which are outnumbered by other non-neoplastic cells in the same tissue, is supported by this case. This finding was preliminarily termed "occult" mastocytosis.

Within the past 10 years, a new range of knowledge has been achieved in the field of amyloidosis, especially with regard to pathogenesis, diagnosis and therapy. Amyloidosis leads to variable and distinct symptoms and is caused by different underlying conditions. Some amyloidoses are acquired secondary to a chronic condition; others are caused by genetic mutations. Amyloid and amyloidosis occur more frequently than they are perceived. Among the frequent localized forms are the cerebral amyloidosis linked to Alzheimer disease (AD) and the pancreatic amyloidosis linked to diabetes mellitus. Among the most frequent systemic (extracerebral) forms is AL amyloidosis, which often has a poor prognosis and if untreated can rapidly lead to death. Systemic amyloidosis that happen at infancy are mainly AA amyloidosis that can progress to death already at early or at middle adulthood. Amyloidosis can be treated but therapeutic success significantly depends upon early diagnosis and proper classification of the amyloid type. It is mandatory that differential diagnosis demonstrate the presence of amyloid and clearly identify the type of the disease. Development of methods and techniques have contributed to improvements in the diagnosis and treatment. Early diagnosis and proper classification of amyloid is decisive for therapeutic options and upon them depend quality of life and mortality. The therapeutic spectrum is various and includes organ transplantation, chemotherapy, and anti-inflammatory strategies. Gene therapy and biological active substances have to be considered in the near future.

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.

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.

The structure of the normal adrenal cortex is changed by stimulating hormones (ACTH) and inhibiting hormonal drugs (especially glucocorticoids). ACTH induces hyperplasia and lipid depletion in the fascicular and reticular zones, whereas glucocorticoids lead to atrophy and lipid accumulation in both zones. In animal experiments, the adrenostatic drug mitotane causes shrinkage of the cells of the fascicular and reticular zones, whereas metyrapone induces a decrease in the steroid producing organelle system and aminoglutethimide leads to an increase in lipids. In the therapy of patients with adrenocortical cancer, mitotane can cause an increase in of necrosis and fibrosis, but also in intracellular lipid. The ultrastructure shows increased liposomes, more pigment-rich lysosomes and laminated bodies.

Radiation therapies of pituitary adenomas induce an increase in fibroses and nuclear pleomorphism. Most growth hormone (GH) secreting pituitary adenomas react to somatostatin analogues by a distinct decrease of GH secretion. In two thirds, levels of IGF-1 can be normalized. Some cases show a shrinkage of adenomas that correlates with fibrosis of the tumor. With these drugs, thyroid stimulating hormone secreting adenomas can also be treated. Prolactin secreting adenomas are mostly treated primarily with dopamine agonists. Up to 90% of cases show a strong decrease in hormone secretion and a distinct shrinkage of the adenomas based on strong decrease in adenoma cell volume. Long-term medication with high doses of glucocorticoids induces Crooke's cells in the anterior pituitary. These are suppressed ACTH cells and characterized by increased numbers of large lysosomes and dense bundles of cytofilaments.

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.

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.

A 61 years old female was treated by total lumpectomy due to a palpable and radiologically demonstrable tumor measuring 22 cm in diameter in the left breast. Two different but directly neighboured malignant tumours were found: a poorly differentiated leiomyosarcoma and a well differentiated invasive papillary carcinoma of the breast. The latter had metastasized in 4 axillary lymph nodes. Three months after surgery the patient died. Post-mortem studies showed many metastases of the leiomyosarcoma in both lungs, the heart, the liver, the left kidney and both adrenals. Cause of death were relapsing pulmonary thrombembolisms. Case reports of leiomyosarcomas following radiotherapy of the breast cancer are published but coincidental occurrence of both metastasizing tumors are so far not known from the literature.

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.

Pituitary adenomas must be clearly differentiated from other tumors of the sellar region (especially meningiomas, granular cell tumors, chordomas and germinomas), which may look very similar. The sub-classification of adenomas depends on the methods used, in particular the immunostaining for pituitary hormones. This sub-classification is not necessary in every case, but must be performed if unusual findings are observed during surgery or if surgery is unsuccessful and radiation or drug-therapy is planned. Special structures and non-immunohistochemical stainings are very helpful for typing adenomas. We differentiated monohormonal densely or sparsely granulated GH-cell adenomas, monohormonal sparsely or very rarely densely granulated prolactin cell adenomas, monohormonal densely or sparsely ACTH-cell adenomas, monohormonal TSH-cell adenomas and FSH/LH cell adenomas from bihormonal adenomas of mammosomatotroph or GH/prolactin cell type or of the acidophil stem cell adenoma type. The number of plurihormonal adenomas decreased with the use of improved monoclonal antibodies. Clinically inactive adenomas are classified as null cell adenomas, oncocytic adenomas or FSH/LH-cell adenomas. These appear as subtypes of one entity deriving from the gonadotroph cell type. Craniopharyngiomas are classified into adamantinous and papillary types, which are not only structurally but also clinically different. If adamantinous craniopharyngiomas show very strongly regressive changes, immunostaining for keratin may be necessary to identify the squamous epithelia for the demonstration of craniopharyngioma.

Adrenocortical tumours have to be differentiated from cortical hyperplasias, medullary tumours and extra-adrenal tumours or metastases. These diagnoses are mostly possible using routine paraffin sections. In some cases, immunostaining for differing cortical and medullary tumours and metastases are necessary. Adrenal hyperplasias can be congenital or acquired. They are diffuse, micronodular or macronodular and may be inactive or induce a cortical hyperfunction. Very rarely, macronodular hyperplasias may transform into autonomous adenomas. Primary, pigmented adrenocortical disease is a rare, special type of primary adrenal Cushing's syndrome, showing many small tumours with pleomorphic cells and an atrophic surrounding cortical tissue. Adrenal adenomas are mostly unilateral and solitary tumours weighing less than 50 g. Adrenal cortical carcinomas are mostly larger. Like the adenomas, they may be inactive and may induce a hypercortisolism, a hyperandrogenism or (very rarely in carcinomas) a hyperaldosteronism. Differentiating cortical adenomas and carcinomas is difficult in some cases but is possible using a diagnostic algorithm. Myelolipomas are benign, inactive tumours composed of mature fat cells and bone marrow cells. They have to be differentiated from adenomas with myelolipomatous metaplasia. Further, rare primary cortical tumours are mentioned.

Most space occupying lesions of the sellar region are tumors (e.g., pituitary adenomas, craniopharyngiomas, but also meningiomas). In approximately 8% of patients with sellar mass lesions, non-neoplastic disorders (e.g., inflammations, cysts, hyperplasia) are causal. Cystic lesions of the pituitary region are classified as Rathke's cysts, colloid cysts, arachnoidal cysts and epidermoid cysts. These have to be differentiated from cystic craniopharyngeomas or cystic pituitary adenomas. Autochthonous inflammations (lymphocyctic hypophysitis, idiopathic granulomatous hypophysitis, xanthomatous and peritumorous hypophysitis) have to be distinguished from generalized diseases involving the pituitary (e.g., sarcoidosis, tuberculosis). Hyperplasia can result in a doubling of pituitary size. Lactotroph and corticotroph hyperplasia are the most common and may be of a diffuse and nodular type. The nodular form of pituitary hyperplasia may show transition into adenoma. Other hyperplasias may be found adjacent to adenomas or other tumours. Furthermore, vascular (aneurysms) and bony lesions (especially fibrous dysplasia) can appear as space occupying lesions of the sellar region.

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.

History and Clinical Findings: A 46-year-old woman was referred to the neurosurgery department for treatment of a macroadenoma of the pituitary. She had complained of recurrent galactorrhoea for 7 years; a hysterectomy was performed 4 years ago. The clinical investigation was unremarkable, except for a slight galactorrheoa on both sides., Investigations: The endocrinological work-up revealed a moderately elevated prolactin level of 3133 mU/l (147 ng/ml) with intact pituitary functions. She had no visual impairment and the MRI depicted a pituitary tumor with a maximal diameter of 1.9 cm and both intra- and suprasellar extension., Diagnosis, Treatment and Clinical Course: The diagnosis of a nonfunctioning macrodenoma with functional hyperprolactinemia was made and a selective transsphenoidal adenomectomy was performed. The primary histology showed a chromophobe adenoma. However, additional immunohistological investigations revealed distinct staining for prolactin. In the meantime, because of persistent galactorrhea and elevated prolactin levels, treatment with cabergolin 0.5 mg/week was started. This stopped galactorrhea and normalized the prolactin levels. A follow-up MRI after 3 months of treatment showed a significant shrinkage of the residual tumor., Conclusion: This case demonstrates that the differential diagnosis of macroprolactinoma with low secretory activity and functional hyperprolactinemia is very difficult preoperatively in individual cases. This is relevant because macroprolactinomas with low secretory activity can also be treated successfully with dopamine agonists. We therefore suggest a drug treatment trial with dopamine agonists in all macroadenoms with hyperprolactinemia, particularly in those with prolactin levels above 2000 mU/l (100 ng/ml).

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.

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.

Leiomyomas are benign tumors that can arise in the smooth muscle and can appear practically everywhere; hence, they must be taken into consideration as a rare possibility in the differential diagnosis of numerous tumors. While leiomyomas of the peripheral vessels are a relatively common finding, they are rarely found in the central vessels. Only a few cases of leiomyomas in the vena cava are known. In contrast to malignant leiomyosarcomas, leiomyomas usually grow towards the lumen. We report on the rare case of a leiomyoma in the inferior vena cava that appeared in the image to be located in the adrenal gland. Therefore, transperitoneal extirpation of the site was undertaken. It was only during surgery that a tumor emanating from the vessel wall became apparent. Thus, after an initial laparoscopic approach it became necessary to change to open resection of the tumor with cavotomy and resection of the vessel wall. The histopathological work-up revealed a benign leiomyoma and further imaging diagnostics gave no indication for the presence of metastases.

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.

The HER-2/neu protein is overexpressed in many human carcinomas obtained from different tissues and may represent a useful target for therapy with the commercially available monoclonal antibody trastuzumab (herceptin). Novel therapeutic options are needed for metastasized adrenocortical cancer. Therefore, we studied expression of the HER-2/neu cell surface receptor protein using three different antibodies in 12 adrenal adenomas, 17 adrenocortical carcinomas and 5 pheochromocytomas. Normal adrenals (n = 5) served as controls. One adenoma showed very weak membranous immunostaining with the Dako antibody, two others showed a nonspecific cytoplasmic staining pattern. A nonspecific reaction in the cytoplasm was demonstrable in seven carcinomas with the Novocastra antibody. In all pheochromocytomas, a granular intracytoplasmic and, rarely, slightly membranous immunostaining with the Dako antibody was found. From our data we conclude that specific and significant membranous immunostaining indicating strong overexpression (grade 3) of HER-2/neu protein is not present in adrenocortical tumors. The granular cytoplasmic immunostaining of the medulla may be helpful for differentiation of adrenocortical tumors from pheochromocytomas.

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.

Basic principles of classification of tumors of the pituitary, parathyroid glands, adrenals, paraganglionic system and endocrine pancreas and the differential diagnosis from non-endocrine tumors are presented. There are no uniform criteria of malignancy and common neuroendocrine immunohistological markers for unequivocal identification, as each organ has its own criteria. For pituitary tumors invasive growth is not a sign of malignancy, but only metastases. For tumors of the adrenal cortex a histopathological score has to be used for proving dignity. For pheochromocytomas, structural criteria (mitoses, angioinvasion) and immunostaining (S-100 protein, p53, Ki-67) are important. Endocrine tumors of the pancreas behave differently if they are angioinvasive or if they show more than two mitoses per 10 HPF, more than 2% Ki-67 positive nuclei or a size of more than 2 cm in diameter. They are malignant if gross local invasion or metastases are demonstrable. Clinical data have to be included in pathohistological reports. In many cases immunostaining in addition to structural analysis will be necessary.

Immunostaining of CD markers in normal pituitary cells has been reported, but a study of these markers in pituitary adenomas has not been done. The expression of CD 3, CD 8, CD 15, CD 20, CD 30, CD 43, CD 45R0, CD 45 R, CD 79 alpha, and VS-38c was investigated in a collection of 65 pituitary adenomas of various types. CD 3 was present in 75%, CD 8 in 18.5%, CD 15 in 12.3%, CD 20 in 66.1%, CD 30 in 10.8%, CD 43 in 10.8%, CD 45 RO in 72.3%, CD 45 R in 16.9%, CD 79alpha in 0% and VS-38 c in 44.6%. Densely granulated GH cell adenomas expressed CD 3, CD 20, CD 45 RO, and CD 45 R, but no other markers. Sparsely granulated GH cell adenomas showed CD 3, CD 8, CD 20, CD 43, and CD 45 RO. Mixed GH/prolactin cell adenomas contained CD 3, CD 8, CD 20, CD 30, CD 45RO, CD 45 R, and VS-38c. Mammosomatotroph cell adenomas were positive only for CD 3, CD 8, CD 20, CD 43, and CD 45 RO. Prolactin cell adenomas expressed CD 3, CD 8, and CD 20. ACTH cell adenomas showed CD 3, CD 15, CD 20, CD 30, CD 45 RO, CD 45 R, and VS-38c. TSH cell adenomas contained CD 3, CD 8, CD 15, CD 20, CD 45 RO, and VS-38c. Gonadotroph cell adenomas were positive for CD 3, CD 8, CD 20, CD 45 RO, CD 45 R, and VS-38c. Alpha-subunit-only adenomas expressed CD 3, CD 8, CD 15, CD 20, CD 30, CD 45 RO, and VS-38c. Plurihormonal adenomas contained CD 3, CD 8, CD 20, CD 30, CD 43, CD 45 RO, CD 45 R, and VS-38c. Oncocytic adenomas were positive for all markers except CD 45 RA and CD 79 alpha. We conclude that the spectra of different adenoma types expressing CD markers varies greatly and that significant correlations do not exist, although noninvasive adenomas appear to express CDs more frequently than invasive adenomas. We have no clear-cut explanations for the various expressions and suggest that it may be a sign of local inter-actions between the immune system and pituitary adenomas.

The management of adrenocorticotropic hormone (ACTH)-dependent Cushing's disease implies difficulties in the differential diagnosis, in the detection of minute pituitary adenomas, as well as in the radical removal of invasive adenomas. Magnetic resonance imaging (MRI) is unspecific and often negative in minute adenomas of three or less millimeters diameter. The trias of detectable ACTH, suppression of cortisol in the high-dose dexamethasone test, and stimulation in the corticotropin-releasing-hormone (CRH)-test has a high accuracy to prove pituitary dependency. In unclear cases, the use of inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS) for the exclusion of ectopic ACTH-syndrome is currently advised especially in cases where cranial MRI is negative. The reliability of these methods to localize the mostly lateralized microadenomas is still discussed. Transsphenoidal microsurgical adenomectomy, the accepted primary therapy of Cushing's disease, has been published from experienced pituitary centers with remission rates ranging from 70% to 98% in the last decade. False diagnosis (pseudo-Cushing, ectopic ACTH-syndrome), incorrect adenoma localization by IPSS or CSS, and the rate of minute or non-resectable invasive tumors influence the results. The handling of minute specimen implies problems for surgeon and pathologist. Intraoperative tumor localization was improved by ACTH measurement from the cavernous sinus and the adenoma itself, by cytology, and frozen sections. The histology of the anterior lobe (rate of Crooke's cells) bears information of clinical relevance. Invasive macroadenomas may deserve repeat microsurgery, medical treatment, and radiosurgery.

In situ hybridization (ISH) enables the visualization of specific mRNA for pituitary hormones. Our collection consists of 40 surgically removed pituitary adenomas that were classified as follicle stimulating hormone/luteinizing hormone (FSH/LH) cell adenomas by structure and by immunostaining (IH) for all pituitary hormones. All forty adenomas were regarded as clinically inactive. The aim of our study was to examine nonfunctioning adenomas by ISH for demonstration of mRNAs for all pituitary hormones. The results were compared with proliferation markers, invasiveness and clinical data. ISH detected signals for all pituitary hormones at a range of 30% for prolactin (PRL) to 85% for proopiomelanocortin (POMC). mRNA for beta-FSH was detected in 70% and beta-LH mRNA in 43% of adenomas. Thirty-three percent of adenomas revealed negative mRNA detection for beta-LH but positive hormone content. The majority of adenomas (75%) expressed more than two mRNAs simultaneously, mostly the combination of POMC mRNA together with beta-FSH mRNA and one to four others. Comparison with clinical data showed no significant differences except for one adenoma with a high Ki-67 index (> 2.1% positive nuclei). This adenoma showed very high signals for PRL and beta-TSH mRNA.

Background: The aim of this study was to determine the hormones produced in pituitary gland tumours (TM) following fractionated external irradiation in rats. The TM arose in the course of studies on other questions of radiation effects., Methods: The left neck and skull base of sixty female Wistar rats, 3 to 4 months of age at the beginning of the external irradiation, were subjected to roentgen rays exposure, fractionated to 2 Grays daily, either up to 20, 40 or 60 Gy. The midline of the neck and skull was always inside the radiation field. The animals were sacrificed either 6 months or 12 months after completion of the randomly assigned irradiation protocol. Five non-irradiated rats served as controls., Results: No TM developed in the non-irradiated animals. Out of 60 irradiated rats 9 developed a pituitary TM (15%). In remnants of the normal adenohypophysis we revealed immunohistochemical reactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid stimulating hormone (TSH), and follicle stimulating hormone (FSH). In the radiation-induced adenomas, 4 TM were immuno-reactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The TM did not react with anti-ACTH and anti-LH (luteinizing hormone) anti-sera., Conclusions: Obviously, irradiation accelerates the development of pituitary gland adenomas. In this series the TM were predominantly incidental findings at necropsies after pretermed follow-up intervals with a variety of hormone-producing cells. On the other hand, four of nine TM were null adenomas. Necropsies of the brain should be carried out routinely in irradiation studies of the skull.

Chordoma is the fourth most common malignant primary neoplasm of the skeleton and almost the only one showing a real epithelial phenotype. Besides classic chordoma, so-called chondroid chordoma was described as a specific entity showing cartilage-like tissue within chordomatoid structures. However, since its first description, strongly conflicting results have been reported about the existence of chondroid chordoma and several studies suggested chondroid chordomas being in fact low-grade conventional chondrosarcomas. In the present study, we used cytoprotein expression profiling and molecular in situ localization techniques of marker gene products indicative of developmental phenotypes of chondrocytes to elucidate origin and biology of chondroid chordoma. We were able to demonstrate the chondrogenic potential of chordomas irrespectively of the appearance of overt cartilage formation by identifying the multifocal expression of type II collagen, the main marker of chondrocytic differentiation. Additionally, the cartilage-typical large aggregating proteoglycan aggrecan was present throughout all chordomas and, thus, a very characteristic gene product and marker of these neoplasms. Biochemical matrix composition and cell differentiation pattern analysis showed a high resemblance of classic chordomas and in chordoid areas of chondroid chordomas to the fetal chorda dorsalis, whereas chondroid areas of chondroid chordomas showed features similar to adult nucleus pulposus. This demonstrates on the cell function level the chondrocytic differentiation potential of neoplastic chordoid cells as a characteristic facet of chordomas, mimicking fetal vertebral development, ie, the transition of the chorda dorsalis to the nucleus pulposus. Our study firmly establishes a focal real chondrocytic phenotype of neoplastic cells in chordomas. Chondroid chordoma is neither a low-grade chondrosarcoma nor a misnomer as discussed previously.

The oncogenes cyclin D1 and D3 are overexpressed in many tumors. Topoisomerase II alpha is found in proliferating cells. The immunohistological expression of cyclin D1, cyclin D3, and Topoisomerase II alpha was studied in a collection of 60 clinically inactive surgically removed pituitary adenomas of the follicle-stimulating hormone/luteinizing hormone (FSH/LH) cell complex (20 null cell adenomas, 20 oncocytomas, and 20 FSH/LH cell adenomas) for correlation with other proliferation markers (Ki-67, PCNA) and with clinical data. Whereas cyclin D1 was positive only in one invasive null cell adenoma (1.7%) with some p53-positive nuclei, cyclin D3 was overexpressed in the nuclei of 41 tumors (68%). Topoisomerase II alpha was demonstrated in the nuclei of 42 adenomas (70%) with no significant differences discernible between the three adenoma subtypes. There was no significant correlation to the time of development of tumor symptoms, but a correlation of Topoisomerase II alpha with cyclin D3 and the proliferation marker Ki-67 (Mib1). From these data we conclude that cyclin D3 and Topoisomerase II alpha appear to be additional markers for proliferation which can be used for prognosis index in surgical pathology of the pituitary.

Null cell adenomas and oncocytomas are clinically inactive adenomas of the pituitary gland. They do not show any significant hormone content detectable by immunohistochemistry. This study aimed at demonstrating mRNAs for all main pituitary hormones in 32 null cell adenomas and 31 oncocytomas by non-isotopic in situ hybridization using digoxigenin-labeled oligonucleotide probes. The results were compared with immunohistochemical and clinical data. Immunohistochemistry (ABC method) was done with monoclonal antibodies against PRL, GH, FSH, LH, TSH, ACTH, alpha-subunit, and Ki-67 (mib-1). The signals for hormone production were detected in both adenoma types in a range from 42% for GH in oncocytomas to 78% for beta-FSH in null cell adenomas. However, these signals are apparently not effective on hormone production, as was shown by almost negative immunostaining. Owing to the simultaneous detection of at least two mRNAs in 78% of null cell adenomas and in 94% of oncocytomas, we assume that both tumor types originate from pluripotential precursor cells that are capable of producing various hormones. According to our data, it is unlikely that the signals influence the clinical behavior.

The present study was designed to investigate the incidence and immunohistochemical characteristics of pituitary tumors in the elderly. In our surgical collection of 1925 cases, we examined tumor tissue from 15 patients over 80 years of age. Pituitaries obtained at routine autopsies from 692 subjects over 80 years of age were also investigated. Of the 15 surgical cases studied, the majority of patients presented with chiasmatic syndromes, likely caused by macroadenomas. Gonadotroph adenomas were the most frequently diagnosed tumor type, followed by null-cell adenomas and oncocytomas. There is only one case with GH cell adenoma. Among 692 autopsy cases, 79 (11.4%) pituitaries were found to contain adenomas in the anterior lobe. In one pituitary, two separate adenomas were detected, hence the number of adenomas in our material was 80. All autopsy cases were microadenomas except one. The mean diameter of adenomas was 2.2 mm. ACTH cell adenomas were the most frequently diagnosed tumor type, followed by PRL cell adenomas and null cell adenomas. The occurrence of pituitary adenomas discovered after routine autopsy in the elderly was common, although these tumors were not found frequently in surgical cases over 80 years of age. Our immunohistochemical study revealed that many tumors contained one or more than one anterior pituitary hormone, although almost all pituitary adenomas were considered to be clinically inactive in surgical and autopsy cases.

The ZAC gene encodes a new zinc-finger protein that concomitantly induces apoptosis and cell cycle arrest and localizes to chromosome 6q24-q25, a well-known hot spot related to cancer. ZAC is highly expressed in the anterior pituitary gland, and its ablation by antisense targeting promotes pituitary cell proliferation. Here we investigate ZAC status in pituitary tumors to evaluate its role in pituitary tumorigenesis. Interest ingly, a strong reduction or absence of ZAC mRNA and protein expres sion was detected in nonfunctioning pituitary adenomas, whereas in clin ically active pituitary neoplasias, the decrease in ZAC expression was variable. Loss of expression was not associated with a mutation of the ZAC gene. Our observations suggest that alternative mechanisms of gene inactivation and/or altered regulation of the ZAC gene occur in nonfunctioning pituitary adenomas.

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.

Tumours in the adrenals originate from the adrenal cortex, the adrenal medulla or as metastases from extra-adrenal primaries. Differentiating between these three groups is the first task a pathologist has to tackle when dealing with specimens from the adrenal region. Whereas this is possible in every case with total removal of the adrenal tumour it may be impossible in fine needle biopsies of such tumours. The second great problem is the dignity of adrenal tumours, which cannot be determined in many adrenomedullary and some adrenocortical tumours. Immunostainings are helpful but the basic method remains the histopathological examination of paraffin sections. This review gives an update of pathological findings in several adrenal tumour entities, and provides guidelines for the diagnosis of these tumours in the light of recently published data.

Introduction: The aim of this study was to investigate the hormone production in pituitary gland tumors following fractionated external irradiation in rats., Materials and Methods: Sixty female Wistar rats 3 to 4 month of age at the beginning of the experiments, were subjected to fractionated roentgen-rays exposure, 2 Grays (Gy) daily, either up to 20, 40 or 60 Gy. The animals were sacrificed either 6 month or 1 year after completion of the randomly assigned irradiation protocol., Results: We found 9 pituitary tumors in 60 irradiated rats (15%). All tumors proved to be adenomas. Immunohistochemical analysis of hormone production in remnants of the normal adenohypophysis revealed immunoreactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH). In adenomas, 4 cases were immunoreactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The tumors were not reactive with anti-ACTH and anti-LH (luteinizing hormone)., Discussion: We concluded that irradiation accelerates the development of pituitary gland adenomas. In our series these tumors were predominantly incidental findings at necropsies after pre-termed follow-up, with a variety of hormone producing tumor cells. However, 4 of 9 tumors in our study were not producing hormones.

Objective: The goal of this study was to evaluate the efficacy and safety of transsphenoidal pituitary surgery for elderly patients, using improved techniques of the past decade., Methods: We retrospectively analyzed 32 surgically treated cases of clinically nonsecreting pituitary adenomas in patients more than 70 years of age (mean, 73.9+/-3.4 yr). These patients were identified in a review of 982 patients with pituitary adenomas who were treated at University Hospital Eppendorf, Hamburg, between January 1991 and November 1999., Results: The mean preoperative duration of symptoms was 1.9 years (2 wk to 11 yr). The chiasmatic syndrome was present for 27 patients (84.4%). All patients underwent transsphenoidal surgery. Seven patients underwent reoperations. Preoperative assessments of anterior pituitary function revealed growth hormone deficiencies for 21 of 27 patients (77.8%), thyroid insufficiencies for 10 of 30 patients (33.3%), and adrenal insufficiencies for 13 of 29 patients (44.8%). Hypogonadism and hyperprolactinemia were observed for 76.7% and 46.9% of the patients, respectively. All tumors were macroadenomas, ranging from 18 to 50 mm (average, 33.6 mm) in size, including 7 enclosed and 25 invasive adenomas. Complete microscopic tumor resection was achieved in 24 cases, and subtotal removal was performed in 8 cases. There were no severe perioperative complications. In the cases involving hyperprolactinemia, serum prolactin levels were normalized for 8 of 11 patients (72.7%). Normal thyroid function was recovered for 1 of 10 patients (10.0%) with preoperative hypothyroidism. However, growth hormone or adrenal insufficiencies persisted for all patients with preoperative insufficiencies. Visual disturbances were improved for 19 of 23 patients (82.6%). All patients recovered well after surgery, with an average hospital stay of 16.3 days. Histological and immunohistochemical studies demonstrated gonadotroph adenomas in 56.7% of cases, null-cell adenomas in 26.7%, and oncocytomas in 13.3%., Conclusion: Surgical treatment of nonsecreting pituitary adenomas causing visual disturbances is standard, even for elderly patients. In this series, transsphenoidal surgery was a safe procedure, with minimal morbidity and excellent tolerance. Age alone is not a contraindication for active treatment, particularly with transsphenoidal surgery.

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma, and hypersecretion of GH-releasing hormone (GHRH) from a hypothalamic or neuroendocrine tumor accounts for other cases. The authors report on the unusual association of acromegaly with a granular cell tumor of the neurohypophysis. A 42-year-old woman with a 10-year history of acral enlargement, headache, and menstrual abnormalities was referred to our department for a suspected GH-secreting pituitary adenoma. The patient's basal GH levels were mildly elevated at 4.8 microg/L, were not suppressed in response to an oral glucose tolerance test, and increased paradoxically after administration of thyrotropin-releasing hormone. The patient's insulin-like growth factor-1 (IGF-1) level was elevated at 462 microg/L, whereas a magnetic resonance image of the sella turcica revealed an intra- and suprasellar lesion that was compatible with a diagnosis of pituitary adenoma. A transsphenoidal approach to remove the lesion, which was mainly suprasellar, was successful during a second operative attempt, resulting in the clinical and biochemical regression of the patient's acromegaly. Four months postoperatively, the patient's basal GH level was 0.9 microg/L and her IGF-1 level was 140 microg/L. Histological analysis of the operative specimen demonstrated a granular cell tumor of the neurohypophysis, which when stained proved negative for pituitary hormones and GHRH. This case represents the first reported association between a granular cell tumor of the neurohypophysis and acromegaly. Granular cell tumor of the neurohypophysis could be added to the restricted list of neoplastic causes of acromegaly secondary to hypersecretion of a GH-releasing substance.

Pituitary necroses develop from the interruption of circulation in the pituitary stalk, especially due to shock, trauma, etc. We studied the incidence, extent, and outcome of necroses in postmortem series from 1991 to 1998 and compared these with the findings in our own study in the 1970s. Necroses were classified into four degrees based on the proportion of anterior pituitary volume: grade I, up to 5%; grade II, 5-10%; grade III, 10-50%; grade IV, more than 50%. The data show a decreased incidence of necrosis, from 7.7% in the 1970s to 3.1% in the 1990s. Scars, indicating former necroses, decreased in incidence from 11.4% to 3.6%. The changes in the four grades of necrosis were: a decrease in grade I from 60% to 41%, a decrease in grade II from 24% to 22%, an increase in grade III from 9% to 17%, and an increase in IV from 8% to 20%. These figures reveal that pituitary necroses became less frequent but more extensive. Necroses of grade IV are generally caused by more than a single cause. The decreased incidence appears to be the consequence of progress in intensive care over the past 20 years, as patients can now survive severe shock longer. The increased frequency of intensive necroses is probably due to the longer period for greater extent of necrosis to develop during intensive care.

The management of pituitary macroadenomas which lead to gigantism may require multiple therapeutical approaches, including medical treatment, surgery, and radiation therapy. Transsphenoidal surgery (TSS) during early childhood that achieves total removal of a growth hormone (GH) secreting tumor is rarely reported. The surgeon is confronted with special problems regarding the infantile anatomy. In this case, a 3.5 year old child, the youngest successfully treated by TSS so far, suffered from a GH- and prolactin (PRL) secreting macroadenoma of the pituitary gland. The girl initially presented with an increasing growth rate, later with breast development, and finally, at the age of 2.8 years, with galactorrhea and secretion of blood from the nipples. Increased levels of GH [122 micrograms/l], insulin-like growth factor (IGF-1) [830 micrograms/l], insulin-like growth factor binding protein 3 (IGFBP-3) [8.6 mg/l] and PRL [590 micrograms/l] were found. MRI scans revealed a macroadenoma of 2.7 cm diameter. An eight-week trial of relatively low dose dopamine agonists led to a reduction of PRL, while the GH- and IGF-1 levels remained unchanged; the tumor showed only little shrinkage. Since there was chiasma compression, we opted for early TSS. A complete tumor removal was achieved despite the difficulties of a narrow approach. After TSS, low levels of GH, IGF-1, and PRL documented a complete tumor removal, but persistent diabetes insipidus and anterior lobe deficits resulted from surgery. In summary, if primary medical therapy alone is unable to adequately reduce hormone hypersecretion and tumor size in early childhood, TSS is recommended. Thus, radiation therapy may be reserved for surgical failure.

Having previously demonstrated the association of basement membrane components (BMC), as well as apolipoprotein E and amyloid in growth hormone (GH)-producing pituitary adenomas, the aim of this study was to further analyze this relationship at the ultrastructural level. Ultrathin sections from four amyloidotic sparsely granulated monohormonal GH-producing adenomas previously investigated light microscopically were selected. Immunoelectron microscopy was performed, using a single labeling postembedding on-grid Protein-A gold method with antisera directed against laminin, fibronectin and apolipoprotein E. In all four adenomas, anti-laminin, anti-fibronectin, and anti-apolipoprotein E reacted with amyloid fibrils. No BMC were demonstrated between amyloid deposits, making it likely that synthesis and deposition of BMC may be secondary to the deposition of amyloid. The intimate spatial relationship between BMC as well as apolipoprotein E and amyloid fibrils may indicate morphological evidence of a particular arrangement of amyloid components in GH-secreting adenoma amyloid and a pathophysiological link.

History and Findings: A 57-year-old woman had an ACTH-producing pituitary adenoma twice resected, followed by bilateral adrenalectomy for recurrent hypercortisolism. She subsequently developed a secondary postadrenalectomy syndrome (Nelson's tumour) which required further surgery and radiotherapy. The patient now presented for elucidation of a space-occupying lesion in the liver, found incidentally on abdominal ultrasonography., Investigations: Immunocytochemistry of the liver biopsy revealed ACTH-producing cells that were structurally identical to the cells found in the specimen resected at the previous operation. Changes were also found in the lower thoracic vertebrae, suspicious of metastases, thus suggesting a metastasizing hypophyseal carcinoma. RESULTS AND COURSE: Resection of the primary tumour and subsequent radiotherapy had arrested the corticotropic, thyrotropic, and gonadotropic functions of the pituitary, which had been adequately treated by administration of the corresponding hormones. Ocreotide, bromocriptin or cytostatics were not given because of their reported doubtful efficacy. At the time of diagnosis of the malignancy a curative operation on the liver or palliative embolization of the liver metastases were not possible because of their number and size. The bone metastases were managed palliatively by radiotherapy., Conclusion: No curative treatment has been found for the 66 cases of hypophyseal carcinoma reported so far. Screening investigations in patients with operated pituitary adenoma with the aim of eliciting an early diagnosis of possible malignancy cannot, therefore, be recommended, particularly since renewed tumour growth and local invasiveness do not constitute criteria for the diagnosis of pituitary carcinoma.

Background: Microsurgical selective adenomectomy is the best established method available for the treatment of Cushing's disease. However, this surgical method warrants still more efforts to improve the results in minute microadenomas. In this paper the authors evaluate a method of intraoperative cytological investigations during transsphenoidal surgery., Method: Between January 1997 and September 1999, transsphenoidal surgery was performed in 75 patients with the diagnosis of Cushing's disease. Fifty-one cases of proven microadenomas were reviewed., Findings: Of 51 cases, 33 tumors were 3 mm or less in diameter, here after called minute adenomas. In 49 of 51 (96.1%) microadenomas, adenoma tissue was identified by intraoperative cytological techniques. Postoperatively, only 35 of 51 ACTH-secreting microadenomas (68.6%) were confirmed by immunostaining methods. This lower percentage was most probably due to the small amount of tissue obtained. Therefore, in 14 cases (including 12 minute adenomas) the presence of the adenoma was only proven by cytological preparation and clinical outcome. The sensitivity of cytological preparations in cases of confirmed Cushing's disease was 100%., Interpretation: The method described here was particularly well suited for the intraoperative discrimination and documentation of minute adenomas. Cytological preparation appears to be effective in improving the adenoma finding rate and the surgical outcome in cases of Cushing's disease.

Although androgen receptors have been identified in normal gonadotroph and somatotroph cells of the pituitary, immunohistochemical studies have failed to reveal these receptors in pituitary adenomas so far. Using a monoclonal antibody to androgen receptor in our series of 60 adenomas of the gonadotroph cell complex (20 FSH/LH cell adenomas, 20 null cell adenomas, 20 oncocytic adenomas), only one null cell adenoma showed strong nuclear immunostaining. All the other antibodies were completely negative. The significance of this finding in correlation with clinical data is still unclear, although it may be associated with more rapid tumor growth. In paraadenomous tissue, some normal gonadotrophs expressed the androgen receptor.

Adenoma tissues from 309 patients with active acromegaly was examined by routine light microscopy and immunohistochemistry, and selectively by electron microscopy. All adenomas were immunoreactive for growth hormone. Eighty-seven adenomas were monohormonal (28%), 58 were bihormonal (immunoreactive for growth hormone and prolactin) (19%), and 157 adenomas were plurihormonal (51%), with positivity for glyco-proteins and/or their α-subunit as well. The mean tumor size was significantly greater in monohormonal adenomas than in other adenoma types. There was no difference in invasiveness among the various adenoma types. Younger patients showed invasive tumor growth more often. Patients with densely granulated GH cell adenomas had a significantly longer duration of symptoms compared to patients with other adenoma types. More than half of the patients with sparsely granulated GH cell adenomas had a duration of less than 5 yr. There was no correlation between duration of symptoms and tumor size. The preoperative mean GH level was significantly higher in patients with sparsely granulated GH cell adenomas than in those with mixed GH/PRL cell adenomas. The preoperative mean PRL level was significantly higher in patients with bihormonal adenomas than in those with plurihormonal adenomas. There was an inverse correlation between age and preoperative GH and PRL levels. No linear correlation was found between preoperative basal GH and PRL levels. Monohormonal adenomas presented more often with suprasellar and/or parasellar extension than other adenoma types. Our data suggest a positive correlation between tumor extension and preoperative GH and PRL levels. Patients with plurihormonal adenomas were significantly older than patients with sparsely granulated GH cell adenomas and mixed GH/PRL cell adenomas. No significant difference was found between the various adenoma types and the extent of surgical removal, which depends on the degree of invasiveness, tumor size, and extrasellar tumor extension.

Case history, light and electron microscopic findings of a case of a lymphocytic hypophysitis in coincidence with a suprasellar germinoma in a 12-year-old girl are reported. The girl presented with a long time case history of diabetes insipidus and subsequent panhypopituitarism. Two years after the diagnosis of diabetes insipidus magnetic resonance imaging (MRI) showed a tumorous enlargement of the sellar content and pituitary stalk. A transnasal exploration was initially performed and revealed a lymphocytic hypophysitis. Light microscopy showed a dense infiltration of mature lymphocytes and plasma cells in the interstitium of the anterior pituitary gland. The stalk area could not be exposed to exclude a germinoma. One year later the lesion relapsed despite dexamethason therapy and a second operation by another neurosurgeon had to be performed. Light microscopy showed lymphocytic infiltrates, fibrosis and necrosis. The diagnosis was a lymphocytic hypophysitis again. Though transcranially exposed only pituitary tissue was removed. No infundibular mass became visible at surgery as shown by MRI. The girl developed five months later multiple cerebral lesions, which revealed to be a germinoma. Lymphocytic hypophysitis in children is very rare and a coincidence with a germinoma has not been described from histopathological aspect until now. The origin of the pituitary infiltration is discussed.

160 clinically non-secreting pituitary adenomas were examined in regard to their expression of the markers PCNA, bcl2, Ki 67 in the mib-1 modification and p53 which are still under investigation for their relevance to cell proliferation. The series contained 60 null cell adenomas, 60 oncocytomas and 40 gonadotroph adenomas. The groups that showed a definitely negative and definitely positive staining were evaluated in regard to their further characteristics such as size, invasiveness and recurrence. PCNA showed a highly represented immunostaining index throughout the groups, but not correlation between the PCNA index and an increased recurrence rate could be found. The staining for bcl2 was only rarely positive and only in a small number of cells. No correlation with the clinical data could be seen. We found a significant higher rate of staining in the invasive adenomas in the group of null cell adenomas and oncocytomas for Ki 67, especially in those adenomas expressing p53. p53 positivity was restricted to the invasive adenomas but was found only in 20% of all invasive adenomas. These data confirm in a sufficiently large series of clinically endocrine inactive pituitary adenomas, that p53 and Ki67 immunohistology is useful in evaluating the aggressive behavior of clinically silent pituitary adenomas. Nevertheless, negative results do not exclude clinically relevant invasive behavior.

Unlabelled: We report the clinical course of a prepubertal girl with central diabetes insipidus (DI) and consequent panhypopituitarism evolving over a period of 10 years due to lymphocytic hypophysitis and subsequent germinoma. Two years after the diagnosis of central DI was established, MRI revealed a thickened pituitary stalk. Later pituitary enlargement and increasing thickening of the pituitary stalk impinging on the optic chiasm required a trans-sphenoidal biopsy which disclosed active hypophysitis with lymphocytic infiltrates and necrosis. High dose dexamethasone treatment only temporarily halted the disease process. Therefore, stereotactic radiation therapy was performed as a rescue treatment and MRI findings almost reversed. However, the subsequent MRI showed multiple intracranial lesions identified histologically as a germinoma and a standard chemotherapy and radiation was performed., Conclusion: The diagnosis of diabetes insipidus in children requires long-term follow up beyond the pubertal age in order to establish the underlying cause. In contrast to lymphocytic hypophysitis in adults, lymphocytic hypophysitis in prepubertal children may represent the first sign of a host reaction to an occult germinoma.

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in < or = 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.

Pituitary adenoma tissue from patients with acromegaly (n = 286) was obtained by surgery and examined for folliculo-stellate cells by immunostaining for S100 protein. The number of immunostained cells varied from one adenoma to another. A hundred and ninety-eight pituitary adenomas (69%) contained S100 protein positive cells corresponding to folliculo-stellate cells (FSC): in 100 cases (35%), only few sparse FSC were found, in 43 cases (15%) FSC were scattered throughout the adenoma, and in 55 cases (19%) there was an abundance of FSC. There were no significant differences regarding sex or age of the patients. The relative amount of FSC vaired among different adenoma types. Plurihormonal adenomas showed the highest FSC density, whereas the majority of monohormonal adenomas contained only few or no FSC. Patients with pituitary adenomas containing scattered FSC had a significantly higher preoperative mean GH level than patients with pituitary adenomas not having FSC. There was a negative correlation between the FSC density in adenoma tissue and the preoperative mean PRL level. There was no correlation between the tumour size and the amount of FSC. Our data indicate no effect of the duration of symptoms on the FSC density and do not suggest a correlation between FSC density and the percentage of a certain hormone-secreting cell type.