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ABSTRACT: The increasing occurrence of incidentally discovered benign adrenocortical tumors has become a clinical dilemma because of
the difficulties in differentiating them from their malignant counterpart. Adrenocortical tumors are associated with familial
cancer syndromes such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, the Carney complex, multiple endocrine
neoplasia type 1, congenital adrenal hyperplasia, and the McCune-Albright syndrome. Genetic events are known to take place
on the chromosomal and gene level in sporadic adrenocortical tumors.
On découvre de plus en plus de tumeur de la surrénale de façon accidentelle. Ceci devient un véritable dilemme clinique car
il est très difficile de distinguer celles qui sont bénignes de celles qui ne le sont pas. Dans cet article, on traite l’association
des tumeurs de la corticosurrénale aux syndromes de cancer familial comme le syndrome de Beckwith-Wiedemann, le syndrome de
Li-Fraumeni, le complexe Carney, le syndrome de néoplasie endocrine multiple du type 1, l’hyperplasie surrénalienne congénitale
et le syndrome de McCune Albright. De plus, on passe en revue les évènements génétiques qui caractérisent les tumeurs de la
corticosurrénale au plan des chromosomes et des gènes.
La creciente frecuencia con que se descubren en forma incidental tumores adenocorticales benignos se ha convertido en un dilema
clínico por razón de las dificultades en diferenciarlos de neoplasmas malignos. En el présente artículo se discute la asociación
de los tumores adrenocorticales con los sindromes familiares de cáncer y con el síndrome de Beckwith-Wiedemann. el síndrome
de Li-Fraumeni, el Complejo de Carney, la neoplasia endocrina múltiple Tipo 1, la hiperplasia suprarrenal congénita y el síndrome
de McCune-Albright. También se revisan los eventos genéticos involucrados. así como los tumores adrenocorticales esporádícos.
World Journal of Surgery 04/2012; 25(7):948-956. · 2.36 Impact Factor
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ABSTRACT: Adenomas of the adrenal cortex cause different disorders depending on the main steroid synthesized and released. The aim of
this research is to increase our understanding of the pathophysiology of steroidogenesis in adrenocortical disorders by comparing
the release of steroids from adrenocortical adenomas in vitro with the messenger RNA (mRNA) expression of steroid synthesizing
enzymes. Fourteen patients with adrenal tumors were included in the present study; nine were diagnosed with primary aldosteronism
and three with Cushing’s syndrome. Two patients had an adrenal tumor discovered on computed tomography (CT) during workup
for an unrelated disease. Serum cortisol, plasma aldosterone, and urinary catecholamines were normal. Tissue was taken for
in vitro steroid release, and aldosterone and cortisol in the medium after a 1-hour incubation were determined. Oligonucleotide
probes with sequences complementary to mRNAs encoding for the steroid synthesizing enzymes 11β-hydroxylase (CYP11B1), 18-hydroxylase
(CYP11B2), 17α-hydroxylase (CYP17), and 21-hydroxylase (CYP21) were synthesized (Genset, Paris, France) and in situ hybridization
was performed. Moderate expression of CYP11B2 and low expression of CYP11B1 were seen in the zona glomerulosa. The zona fasciculata
of the control adrenals expressed a high signal of CYP11B1, whereas the expression of CYP11B2 was very low. There was considerable
variation in aldosterone release from the aldosteronomas, whereas the tumors from the Gushing patients showed no detectable
release of aldosterone. In contrast, tumors from patients with primary aldosteronism, Cushing’s syndrome, and no hyper-function
all had the ability to synthesize and release cortisol in vitro. The highest cortisol release was found in tumors from patients
with Cushing’s syndrome, but also the nonhyperfunctioning tumors and some of the aldosteronomas released significant amounts
of cortisol. The two patients with highest release of aldosterone in vitro showed the highest expression of CYP11B2 and the
lowest expression of CYP11B1 and CYP17. The remaining aldosteronomas had low expression of CYP11B2, similar to the two other
groups. Expression of CYP11B1 was high as expected in the Gushing adenomas, but also the two nonhyperfunctioning tumors and
some of the aldosteronomas showed a moderate expression. Adenomas from Cushing’s syndrome, nonhyperfunctioning adenomas, and
some of the aldosterone- producing adenomas had moderate to high expression of CYP17. This paper presents new means for functional
characterization of adrenocortical tumors. Diagnosis of an aldosteronoma is often difficult, and with the advent of these
methods it is possible to determine the functional capacity of a tumor, once it is removed. This is of special interest if
the patient remains hypertensive postoperatively, and it is not clear whether the patient indeed had a functioning tumor.
Le tableau clínique des adénomes de la corticosurrénale varie selon le type dominant de stéroïde synthétisé et sécrété. Le
but de cet article a été d’améliorer la compréhension de la physiopathogenèse des stéroïdes dans les maladies de la surrénale
en comparant la sécrétion des stéroïdes à partir des adénomes de la corticosurrénale in vitro avec l’expression mRNA des enzymes
de synthèse stéroídien. Quatorze patients ayant une tumeur de la surrénale ont été inclus dans cette étude. On a retenu le
diagnostic d’hyperaldostéronisme primitif chez neuf alors que trois patients avaient un syndrome de Cushing. Deux patients
avaient une tumeur de la surrénale découverte par la tomodensitométrie réalisée pour une pathologie sans rapport. Les taux
sériques de cortisol, d’aldostérone et de catécholamines urinaires étaient normaux. On a déterminé la sécrétion de stéroïdes,
d’aldostérone et de cortisol in vitro après une heure d’incubation du tissu prélevé. Des sondes d’oligonucléotide avec des
séquences complémentaires à l’encodage mRNAs pour les enzymes de synthèse 11-beta-hydroxylase (CYP11B1), 18-hydroxylase (CYP11B2),
17 alpha-hydroxylase (CYP17) et 21-hydroxylase (CYP21) ont été synthétisés (Genset, Paris, France) et une hybridation in situ
a été réalisée. On a trouvé une expression modérée de CYP11B2 et une expression basse de CYP11B1 dans la zone glomérulaire.
La zone fasciculaire des surrénales de contróle a exprimé un signal intense de CYP11B1 alors que l’expression de CYP11B2 était
basse. Il y avait une forte variation en ce qui concernait la sécrétion d’aldostérone à partir des aldostéronomes alors que
les tumeurs des patients ayant un syndrome de Cushing ne sécrétaient pas d’aldostérone. En revanche, les tumeurs provenant
des patients ayant un hyperaldostéronisme primitif, un syndrome de Cushing, sans hyperfonctionnement étaient toutes capables
de synthétiser et de sécréter le cortisol in vitro. Le taux le plus élevé de cortisol a été retrouvé chez les patients ayant
un syndrome de Cushing, mais également chez les patients porteurs de tumeurs non fonctionnelles et chez quelques patients
ayant un aldostéronome. Les deux patients ayant le taux le plus élevé d’aldostérone in vitro avaient également la plus forte
expression de CYP11B2, alors que celles de CYP11B1 et de CYP17 étaient la plus faible. Les autres patients porteurs d’aldostérome
avaient une expression réduite de CYP11B2, similaire aux deux autres groupes. L’expression de CYP11B1 était élevé, comme attendue
dans le syndrome de Cushing par adénome, mais également chez les deux tumeurs non hyperfonctionelles, alors que l’expression
était modérée chez les patients ayant un aldostéronome. L’expression de CYP 17 était modérée à élevée chez les patients ayant
un adénome avec syndrome de Cushing, un adénome non-hyperfonctionnel et dans le cas de quelques adénomes produisant de l’aldostérone.
Dans cet article, on présente de nouvelles modalités pour caractériser la fonction des tumeurs de la corticosurrénale. Le
diagnostic d’un aldostéronome est souvent difficile mais avec ces nouvelles modalités diagnostiques, il est possible désormais
de connatre la capacité fonctionnelle de la tumeur, une fois enlevée. Ceci a un intérét particulier si le patient reste hypertendu
en postopératoire lorsqu’ on ne savait pas en préopératoire si la tumeur était fonctionnelle.
Los adenomas de la corteza suprarrenal ocasionan diferentes alteraciones clínicas según el principal esteroide que sintetizan
y secretan. El propósito del présente trabajo fue incrementar el conocimiento sobre la fisiopatología de la estereidogénesis
en las enfermedades adrenocorticoles comparando la liberation in vitro de esteroides por adenomas adrenocorticales con la
expresión de mRNA de las enzimas sintetizadoras de esteroides. Catorce pacientes con tumores suprarrenales fueron incluidos
en el estudio, nueve con el diagnóstico de aldosteronismo primario y très con síndrome de Cushing. En dos se encontró un tumor
suprarrenal en tomografia computadorizada en el curso del estudio de una enfermedad no relacionada. El cortisol sérico, el
nivel plasmático de aldosterona y las catecolaminas urinarias aparecieron dentro de límites normales. Se tomaron tejidos para
la determination in vitro de liberación de esteriodes y de la presencia de aldosterona y cortisol en el medio luego de una
hora de incubation. Se observé expresión moderada de CYP11B2 y baja expresion de CYP11B1 en la zona glomerulosaa. La zona
fasciculata de las suprarrenales de control expresaron una elevada señal de CYP11B1, en tanto que la expresión de CYP11B2
apareció muy baja. Se observó una variación considerable en la liberación de aldosterona por los aldosteronomas, en tanto
que los tumores de los pacientes con Cushing no demostraron liberación de aldosterona. En contraste, los tumores de pacientes
con aldosteronismo primario, síndrome de Cushing y aquellos sin hiperfunción, todos exhibieron capacidad para sintetizar y
liberar cortisol in vitro. La más alta liberación de cortisol fue hallada en tumores de pacientes con síndrome de Cushing,
pero los tumores no hiperfuncionantes y algunos de los aldosteronomas mostraron liberación significante de cortisol. Los dos
pacientes con la más alta liberación de aldosterona in vitro mostraron también la más elevada expresión de CYP11B2 y la más
baja de CYP11B1 y CYP17. Los restantes aldosteronomas mostraron baja expresión de CYP11B2, similar a la de los otros dos grupos.
La expresión de CYP11B1 apareció elevada, como era lo esperado, en los adenomas de Cushing, pero también en los tumores no
hiperfuncionantes; algunos de los aldosteronomas exhibieron expresión moderada. Los adenomas del síndrome de Cushing, lo adenomas
no hiperfuncionantes y algunos de los adenomas productores de aldosterona exhibieron expresión moderada a alta de CYP17. El
présente artículo muestra nuevas maneras de hacer la caracterización funcional de los tumores suprarrenales. El diagnóstico
de aldosteronoma frecuentemente es difícil y con el advenimiento de estos métodos es posible determinar la capacidad funcional
del tumor que ha sido resecado. Esto es de interés especial cuando el patiente se mantiene hipertenso en el postoperatorio
y no aparece claro si realmente tenía un tumor funcional.
World Journal of Surgery 04/2012; 25(7):957-966. · 2.36 Impact Factor
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ABSTRACT: The purpose of this study was to investigate if the ProMIS™ simulator could serve as a training platform for the da Vinci® surgical system and if this constellation could prove construct validity.
The da Vinci system was connected to the ProMIS simulator, which registered objective data concerning how the surgeon performed in the box environment related to time, path, and smoothness. Five experienced robotic surgeons passed four different surgical tasks with progressive difficulty. A novice group-constituted of 13 consultants and 6 residents, none of them with any previous experience in the da Vinci system-passed the same tasks and the data were compared with the results from the expert group.
A statistically significant difference between experts and novices was demonstrated in all tasks concerning time and smoothness. For the parameter path, significant difference was only noted in the more complex tasks.
Our study showed that ProMis could differentiate between experienced robotic surgeons and novices, thereby proving construct validity. Smoothness appeared to be the most sensitive objective parameter in our study. Tasks with high complexity are recommended when designing the program for robotic training.
Journal of endourology / Endourological Society 11/2010; 25(2):345-50. · 1.75 Impact Factor
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ABSTRACT: Surgery is the only curative treatment for primary hyperparathyroidism. Focused surgical techniques are being practiced with increasing frequency. Preoperative imaging, such as scintigraphy, is a prerequisite for focused surgery. There is controversy about which preoperative imaging method should be used. The sensitivity reported for parathyroid scintigraphy varies considerably. This study was designed to determine the accuracy of the preoperative imaging routinely used at our institution.
This retrospective study included consecutive patients who underwent a routine dual-phase sestamibi-SPECT (single photon emission computed tomography) scintigraphy and subsequent operation with follow-up. Scintigraphy results were evaluated by comparing the results to surgical findings and histopathology.
Two hundred and sixty-four individuals entered the study. Sensitivity for scintigraphy was 84%, specificity 91%, positive predictive value 91%, and negative predictive value 84%.
Sestamibi-SPECT scintigraphy is a sensitive preoperative modality with high positive predictive value. Scintigraphy is a good indicator for when to perform a focused surgical approach and could often correctly guide the actual operation.
Langenbeck s Archives of Surgery 10/2009; 394(5):811-5. · 1.81 Impact Factor
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Cecilia Laurell,
David Velázquez-Fernández,
Kristina Lindsten,
Christofer Juhlin,
Ulla Enberg,
Janos Geli,
Anders Höög, Magnus Kjellman,
Joakim Lundeberg,
Bertil Hamberger,
Catharina Larsson,
Peter Nilsson,
Martin Bäckdahl
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ABSTRACT: Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5-2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.
Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.
Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.
Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.
European Journal of Endocrinology 06/2009; 161(1):141-52. · 3.42 Impact Factor
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ABSTRACT: Distinguishing between adrenocortical adenomas and carcinomas is often difficult. Our aim was to investigate the differences in transcriptional profiles between benign and malignant adrenocortical neoplasms using complementary DNA microarray techniques.
We studied 7 patients with adrenocortical carcinomas and 13 with adenomas. Histopathology was reviewed in all patients; clinical follow-up was at least 1 year. Hybridizations were performed in duplicate against RNA reference. Expression levels were analyzed in the R environment for statistical computing with the use of aroma, limma, statistics, and class packages.
Transcriptional profiles were homogeneous among adenomas, while carcinomas were much more heterogeneous. Hierarchical clustering and self-organizing maps could separate clearly carcinomas from adenomas. Among genes that were most significantly upregulated in carcinomas were 2 ubiquitin-related genes (USP4 and UFD1L) and several insulinlike growth factor-related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among genes that were most significantly downregulated in carcinomas were a cytokine gene (CXCL10), several genes related to cell metabolism (RARRES2, ALDH1A1, CYBRD1 and GSTA4), and the cadherin 2 gene (CDH2).
Through the use of cDNA arrays, adrenocortical adenomas and carcinomas appear to be clearly distinguishable on the basis of their specific molecular signature. The biologic importance of the up- and downregulated genes is yet to be determined.
Surgery 01/2006; 138(6):1087-94. · 3.10 Impact Factor
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ABSTRACT: Several types of endocrine tumors show frequent somatic deletions of the distal part of chromosome arm 11q, where the tumor-suppressor gene SDHD (succinate-ubiquinone oxidoreductase subunit D), constitutionally mutated in paragangliomas of the head and neck, is located. In this study, we screened 18 midgut carcinoids, 7 Merkel cell carcinomas, 46 adrenal pheochromocytomas (37 sporadic and 9 familial), and 7 abdominal paragangliomas for loss of heterozygosity (LOH) and/or mutations at the SDHD gene locus. LOH was detected in 5 out of 8 (62%) informative midgut carcinoids, in 9 out of 30 (30%) sporadic pheochromocytomas, in none of the familial pheochromocytomas (0%), and in 1 out of 6 (17%) abdominal paragangliomas. No sequence variants were detected in the pheochromocytomas or paragangliomas. However, two constitutional putative missense mutations, H50R and G12S, were detected in two midgut carcinoids, which were both associated with LOH of the other allele. The same sequence variants were also detected in two Merkel cell carcinomas. In addition, the S68S polymorphism was found to coexist with the G12S sequence variant in both cases. In conclusion, we show that alterations of the SDHD gene seem to be involved in the tumorigenesis of both midgut carcinoids and Merkel cell carcinomas.
Genes Chromosomes and Cancer 08/2002; 34(3):325-32. · 3.31 Impact Factor
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ABSTRACT: The frequent and generalized chromosomal imbalances that are characteristic of adrenocortical carcinomas suggest that incomplete chromosome segregation often takes place in these tumors. As a step towards elucidating the mechanism behind the multiple numerical chromosomal aberrations, we have evaluated a series of 14 such tumors for centrosome abnormalities using immunohistochemical detection of the gamma-tubulin centrosome component. The proportion of cells with more than the expected number of 2 centrosomes was moderately increased in the 4 adenomas (1-7%), while a high increase was observed in the 10 carcinomas (1-19%), as compared to the normal reference tissues (0.3%) (p<0.001). Similarly, the centrosome amplification tended to be more pronounced in the carcinomas where the aberrant cells carried 3 or 4 positive signals in 9 of the 10 tumors, and 6 signals were recorded in one tumor, while in the adenomas more than 3 signals was only recorded in one of the 4 cases. The findings demonstrate that centrosome amplifications occur frequently in both adrenocortical adenomas and carcinomas, thus supporting its role in driving the tumor development as opposed to being a consequence of it. Furthermore, the more pronounced occurrence in the malignant form as well as in the larger tumors, offers one likely explanation for the increasing generalized aneuploidy observed during the tumor development, and points to new therapeutic strategies aimed at restoring normal centrosome function.
International Journal of Oncology 06/2002; 20(6):1161-5. · 2.40 Impact Factor
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ABSTRACT: In earlier studies a high-molecular-weight (HMW) insulin-like growth factor-II (IGF-II) peptide was identified in adult human pancreas and localized to the insulin-producing B-cells. This peptide has now been investigated in neoplastic insulin cells. Forty endocrine pancreatic tumours and 17 pancreatic adenocarcinomas of ductal type were included in the study. All cases were investigated with immunohistochemical techniques using antibodies to IGF-II, insulin, pro-insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and vasoactive intestinal peptide (VIP). Frozen tissue from nine tumours and two normal pancreatic glands was extracted, gel separated, and quantified using radioimmunoassay. The tumours were also investigated by in situ hybridization. IGF-II-immunoreactive cells were found in nearly all the 18 insulin-producing tumours (16/18), in a minority of the other endocrine tumours, but not in pancreatic adenocarcinomas. All extracts from the endocrine tumours showed varying amounts of IGF-II and had different molecular-weight forms. The immunohistochemical and radioimmunoassay findings are both based on immunological binding and were further confirmed by Northern blot and in situ hybridization. These results show that IGF-II is expressed in insulin-producing tumours as well as in pancreatic tumours producing other peptides, in contrast to normal pancreatic islets where IGF-II is found exclusively in insulin-producing cells.
Apmis 01/2001; 109(2):127 - 140. · 1.99 Impact Factor
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ABSTRACT: The incidental detection of small benign adrenocortical tumors has increased in patients who are investigated with imaging techniques in the upper abdomen. Because these benign lesions are difficult to differentiate from their rare malignant counterparts, the interest to find better tumor markers has increased. In this overview of genetic events in adrenocortical tumors the cancer syndromes Li-Fraumeni, Beckwith-Wiedemann, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, Carney complex, and McCune-Albright are discussed. Moreover, molecular and cytogenetic analysis on sporadic adrencortical tumors indicate that chromosomes 2, 4, 5, 11, 17, and 18 may harbor genes of importance for the malignant transition of this tumor form. Candidate genes such as IGF2, TP53, and ACT-R are located on these chromosomes and have shown alterations.
Current Opinion in Endocrinology Diabetes and Obesity 01/1999; 6(1):70. · 3.62 Impact Factor
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ABSTRACT: Endothelin (ET)-1 is a 21-amino acid peptide with potent vasopressor and vasoconstrictive properties. Biochemical studies
suggest that this peptide occurs in the adrenal cortex, where it appears to influence steroid hormone production and catecholamine
release. Concomitant with our previous immunohistological study, we found ET-1 immunoreactive (IR) cells in human adrenal
cortex and cortical neoplasms, but not in the medulla. These ET-1 IR cells were numerous in adenomas, but were seen only occasionally
in some of the carcinomas. In the present study, the ET-1 IR protein was extracted from normal (n=5) and hyperplastic (n=3) human cortex as well as from cortical adenomas (n=10) and carcinomas (n=5). Its molecular weight, determined by SDS-polyacrylamide gel electrophoresis and immunoblotting, was 9kD, which is lower
than that of prepro-ET-1 (21kD), but larger than that of pre-ET-1 (4.3kD) and ET-1 (2.5kD). The normal cortical specimens,
hyperplasias, adenomas and three of the five carcinomas all contained this distinct band. The two carcinomas lacking it were
associated with Conn’s syndrome. The protein may constitute a protein not previously described, but further studies are needed
to determine its complete structure.
Histochemie 12/1998; 111(1):33-37. · 2.59 Impact Factor
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ABSTRACT: Neuroendocrine differentiation and nerve distribution were studied in sections from human cortex (n=11) and cortical lesions (hyperplasias, n=9; adenomas, n=13; carcinomas, n=14) with four markers, namely chromogranin A(CgA), synaptophysin (SYN), neuron-specific enolase (NSE), protein gene product (PGP) 9.5 and small synaptic vesicle protein (SV)2. All but two cases expressed neuroendocrine differentiation. NSE was the most commonly occurring marker and the NSE immunoreactive cells were detected in normal cortex, mainly in zona glomerulosa, as well as in adenomas and carcinomas. SYN and PGP 9.5 immunoreactive cells were especially prominent in the carcinomas, while SV2 immunoreactive cells were seen mainly in normal cortex. The difference in distribution pattern of the neuroendocrine markers between adenomas and carcinomas was not so distinct that it can be used for histopathological diagnosis. The significance of neuroendocrine differentiation in cortex and cortical lesions is uncertain, but may reflect an involvement in special hormonal functions. No obvious relationship was found between the clinical syndromes and the degree of neuroendocrine differentiation. Three of the neuroendocrine markers also visualized nerve structures. PGP 9.5, which is regarded as the most ‘general’ nerve marker, visualized more nerve structures than did the other markers. Normal cortex contained most immunoreactive nerves, whereas they were less numerous in hyperplasias and sparse or even absent in the neoplasms. The nerves appeared among the parenchymal cells but were particularly prominent around vessels. The results suggest that the cortical nerves influence not only the regulation of the blood supply but also the hormonal regulation at the cellular level.
Apmis 06/1998; 106(7‐12):807 - 817. · 1.99 Impact Factor
