Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications
Identifieur interne : 000336 ( Ncbi/Merge ); précédent : 000335; suivant : 000337Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications
Auteurs : Christian P. Miermeister [Allemagne] ; Stephan Petersenn [Allemagne] ; Michael Buchfelder [Allemagne] ; Rudolf Fahlbusch [Allemagne] ; Dieter K. Lüdecke [Allemagne] ; Annett Hölsken [Allemagne] ; Markus Bergmann [Allemagne] ; Hans Ulrich Knappe [Allemagne] ; Volkmar H. Hans [Allemagne] ; Jörg Flitsch [Allemagne] ; Wolfgang Saeger [Allemagne] ; Rolf Buslei [Allemagne]Source :
- Acta Neuropathologica Communications [ 2051-5960 ] ; 2015.
Abstract
The term
Of the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis.
We determined significant threshold values for p53 (≥2 %; AUC: 0.94) and the mitotic index (≥2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index ≥ 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (
Here we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.
The online version of this article (doi:10.1186/s40478-015-0229-8) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s40478-015-0229-8
PubMed: 26285571
PubMed Central: 4545559
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Miermeister</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Petersenn, Stephan" sort="Petersenn, Stephan" uniqKey="Petersenn S" first="Stephan" last="Petersenn">Stephan Petersenn</name><affiliation wicri:level="1"><nlm:aff id="Aff2">ENDOC Center for Endocrine Tumors, Hamburg & University of Duisburg-Essen, Essen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>ENDOC Center for Endocrine Tumors, Hamburg & University of Duisburg-Essen, Essen</wicri:regionArea><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion></affiliation></author><author><name sortKey="Buchfelder, Michael" sort="Buchfelder, Michael" uniqKey="Buchfelder M" first="Michael" last="Buchfelder">Michael Buchfelder</name><affiliation wicri:level="3"><nlm:aff id="Aff3">Departments of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen</wicri:regionArea><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Fahlbusch, Rudolf" sort="Fahlbusch, Rudolf" uniqKey="Fahlbusch R" first="Rudolf" last="Fahlbusch">Rudolf Fahlbusch</name><affiliation wicri:level="3"><nlm:aff id="Aff4">Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurosurgery, International Neuroscience Institute, Hannover</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Ludecke, Dieter K" sort="Ludecke, Dieter K" uniqKey="Ludecke D" first="Dieter K." last="Lüdecke">Dieter K. Lüdecke</name><affiliation wicri:level="3"><nlm:aff id="Aff5">Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Holsken, Annett" sort="Holsken, Annett" uniqKey="Holsken A" first="Annett" last="Hölsken">Annett Hölsken</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Bergmann, Markus" sort="Bergmann, Markus" uniqKey="Bergmann M" first="Markus" last="Bergmann">Markus Bergmann</name><affiliation wicri:level="3"><nlm:aff id="Aff6">Department of Neuropathology, Klinikum Bremen Mitte, Bremen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neuropathology, Klinikum Bremen Mitte, Bremen</wicri:regionArea><placeName><region type="land" nuts="3">Brême (Land)</region><settlement type="city">Brême</settlement></placeName></affiliation></author><author><name sortKey="Knappe, Hans Ulrich" sort="Knappe, Hans Ulrich" uniqKey="Knappe H" first="Hans Ulrich" last="Knappe">Hans Ulrich Knappe</name><affiliation wicri:level="1"><nlm:aff id="Aff7">Department of Neurosurgery, Johannes Wesling Hospital Minden, Minden, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurosurgery, Johannes Wesling Hospital Minden, Minden</wicri:regionArea><wicri:noRegion>Minden</wicri:noRegion><wicri:noRegion>Minden</wicri:noRegion><wicri:noRegion>Minden</wicri:noRegion></affiliation></author><author><name sortKey="Hans, Volkmar H" sort="Hans, Volkmar H" uniqKey="Hans V" first="Volkmar H." last="Hans">Volkmar H. Hans</name><affiliation wicri:level="1"><nlm:aff id="Aff8">Department of Pathology, Ruhr University Bochum, Bochum, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pathology, Ruhr University Bochum, Bochum</wicri:regionArea><wicri:noRegion>Bochum</wicri:noRegion><wicri:noRegion>Bochum</wicri:noRegion><wicri:noRegion>Bochum</wicri:noRegion></affiliation></author><author><name sortKey="Flitsch, Jorg" sort="Flitsch, Jorg" uniqKey="Flitsch J" first="Jörg" last="Flitsch">Jörg Flitsch</name><affiliation wicri:level="3"><nlm:aff id="Aff5">Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Saeger, Wolfgang" sort="Saeger, Wolfgang" uniqKey="Saeger W" first="Wolfgang" last="Saeger">Wolfgang Saeger</name><affiliation wicri:level="3"><nlm:aff id="Aff9">Departments of Neuropathology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, University Clinic Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Buslei, Rolf" sort="Buslei, Rolf" uniqKey="Buslei R" first="Rolf" last="Buslei">Rolf Buslei</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26285571</idno><idno type="pmc">4545559</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545559</idno><idno type="RBID">PMC:4545559</idno><idno type="doi">10.1186/s40478-015-0229-8</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000131</idno><idno type="wicri:Area/Pmc/Curation">000131</idno><idno type="wicri:Area/Pmc/Checkpoint">000132</idno><idno type="wicri:Area/Ncbi/Merge">000336</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications</title><author><name sortKey="Miermeister, Christian P" sort="Miermeister, Christian P" uniqKey="Miermeister C" first="Christian P." last="Miermeister">Christian P. Miermeister</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Petersenn, Stephan" sort="Petersenn, Stephan" uniqKey="Petersenn S" first="Stephan" last="Petersenn">Stephan Petersenn</name><affiliation wicri:level="1"><nlm:aff id="Aff2">ENDOC Center for Endocrine Tumors, Hamburg & University of Duisburg-Essen, Essen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>ENDOC Center for Endocrine Tumors, Hamburg & University of Duisburg-Essen, Essen</wicri:regionArea><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>Essen</wicri:noRegion></affiliation></author><author><name sortKey="Buchfelder, Michael" sort="Buchfelder, Michael" uniqKey="Buchfelder M" first="Michael" last="Buchfelder">Michael Buchfelder</name><affiliation wicri:level="3"><nlm:aff id="Aff3">Departments of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen</wicri:regionArea><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Fahlbusch, Rudolf" sort="Fahlbusch, Rudolf" uniqKey="Fahlbusch R" first="Rudolf" last="Fahlbusch">Rudolf Fahlbusch</name><affiliation wicri:level="3"><nlm:aff id="Aff4">Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurosurgery, International Neuroscience Institute, Hannover</wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Ludecke, Dieter K" sort="Ludecke, Dieter K" uniqKey="Ludecke D" first="Dieter K." last="Lüdecke">Dieter K. Lüdecke</name><affiliation wicri:level="3"><nlm:aff id="Aff5">Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Holsken, Annett" sort="Holsken, Annett" uniqKey="Holsken A" first="Annett" last="Hölsken">Annett Hölsken</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Bergmann, Markus" sort="Bergmann, Markus" uniqKey="Bergmann M" first="Markus" last="Bergmann">Markus Bergmann</name><affiliation wicri:level="3"><nlm:aff id="Aff6">Department of Neuropathology, Klinikum Bremen Mitte, Bremen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neuropathology, Klinikum Bremen Mitte, Bremen</wicri:regionArea><placeName><region type="land" nuts="3">Brême (Land)</region><settlement type="city">Brême</settlement></placeName></affiliation></author><author><name sortKey="Knappe, Hans Ulrich" sort="Knappe, Hans Ulrich" uniqKey="Knappe H" first="Hans Ulrich" last="Knappe">Hans Ulrich Knappe</name><affiliation wicri:level="1"><nlm:aff id="Aff7">Department of Neurosurgery, Johannes Wesling Hospital Minden, Minden, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurosurgery, Johannes Wesling Hospital Minden, Minden</wicri:regionArea><wicri:noRegion>Minden</wicri:noRegion><wicri:noRegion>Minden</wicri:noRegion><wicri:noRegion>Minden</wicri:noRegion></affiliation></author><author><name sortKey="Hans, Volkmar H" sort="Hans, Volkmar H" uniqKey="Hans V" first="Volkmar H." last="Hans">Volkmar H. Hans</name><affiliation wicri:level="1"><nlm:aff id="Aff8">Department of Pathology, Ruhr University Bochum, Bochum, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pathology, Ruhr University Bochum, Bochum</wicri:regionArea><wicri:noRegion>Bochum</wicri:noRegion><wicri:noRegion>Bochum</wicri:noRegion><wicri:noRegion>Bochum</wicri:noRegion></affiliation></author><author><name sortKey="Flitsch, Jorg" sort="Flitsch, Jorg" uniqKey="Flitsch J" first="Jörg" last="Flitsch">Jörg Flitsch</name><affiliation wicri:level="3"><nlm:aff id="Aff5">Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Saeger, Wolfgang" sort="Saeger, Wolfgang" uniqKey="Saeger W" first="Wolfgang" last="Saeger">Wolfgang Saeger</name><affiliation wicri:level="3"><nlm:aff id="Aff9">Departments of Neuropathology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, University Clinic Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Buslei, Rolf" sort="Buslei, Rolf" uniqKey="Buslei R" first="Rolf" last="Buslei">Rolf Buslei</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author></analytic><series><title level="j">Acta Neuropathologica Communications</title><idno type="eISSN">2051-5960</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Introduction</title><p>The term <italic>atypical pituitary adenoma</italic> (APA) was revised in the 2004 World Health Organization (WHO) classification of pituitary tumors. However, two of the four parameters required for the diagnosis of APAs were formulated rather vaguely (i.e., <italic>“extensive”</italic> nuclear staining for p53; <italic>“elevated”</italic> mitotic index). Based on a case-control study using a representative cohort of typical pituitary adenomas and APAs selected from the German Pituitary Tumor Registry, we aimed to obtain reliable cut-off values for both p53 and the mitotic index. In addition, we analyzed the impact of all four individual parameters (invasiveness, Ki67-index, p53, mitotic index) on the selectivity for differentiating both adenoma subtypes.</p></sec><sec><title>Methods</title><p>Of the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis.</p></sec><sec><title>Results</title><p>We determined significant threshold values for p53 (≥2 %; AUC: 0.94) and the mitotic index (≥2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index ≥ 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (<italic>p</italic> < 0.001); OR 5.2// p53 (<italic>p</italic> < 0.001); OR 3.1// mitotic index (<italic>p</italic> < 0.001); OR 2.1// invasiveness (<italic>p</italic> < 0.001); OR 8.2)) were significant for the group of APAs. Furthermore, we describe the presence of nucleoli as a new favorable parameter for TPAs (<italic>p</italic> = 0.008; OR: 0.4; CI95 %: 0.18; 0.77).</p></sec><sec><title>Conclusions</title><p>Here we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s40478-015-0229-8) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Buurman, H" uniqKey="Buurman H">H Buurman</name></author><author><name sortKey="Saeger, W" uniqKey="Saeger W">W Saeger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Daly, Af" uniqKey="Daly A">AF Daly</name></author><author><name sortKey="Rixhon, M" uniqKey="Rixhon M">M Rixhon</name></author><author><name sortKey="Adam, C" uniqKey="Adam C">C Adam</name></author><author><name sortKey="Dempegioti, A" uniqKey="Dempegioti A">A Dempegioti</name></author><author><name sortKey="Tichomirowa, Ma" 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Acta Neuropathol Commun</journal-id><journal-id journal-id-type="iso-abbrev">Acta Neuropathol Commun</journal-id><journal-title-group><journal-title>Acta Neuropathologica Communications</journal-title></journal-title-group><issn pub-type="epub">2051-5960</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26285571</article-id><article-id pub-id-type="pmc">4545559</article-id><article-id pub-id-type="publisher-id">229</article-id><article-id pub-id-type="doi">10.1186/s40478-015-0229-8</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Miermeister</surname><given-names>Christian P.</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Petersenn</surname><given-names>Stephan</given-names></name><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Buchfelder</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Fahlbusch</surname><given-names>Rudolf</given-names></name><xref ref-type="aff" rid="Aff4"></xref></contrib><contrib contrib-type="author"><name><surname>Lüdecke</surname><given-names>Dieter K.</given-names></name><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Hölsken</surname><given-names>Annett</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Bergmann</surname><given-names>Markus</given-names></name><xref ref-type="aff" rid="Aff6"></xref></contrib><contrib contrib-type="author"><name><surname>Knappe</surname><given-names>Hans Ulrich</given-names></name><xref ref-type="aff" rid="Aff7"></xref></contrib><contrib contrib-type="author"><name><surname>Hans</surname><given-names>Volkmar H.</given-names></name><xref ref-type="aff" rid="Aff8"></xref></contrib><contrib contrib-type="author"><name><surname>Flitsch</surname><given-names>Jörg</given-names></name><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Saeger</surname><given-names>Wolfgang</given-names></name><xref ref-type="aff" rid="Aff9"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Buslei</surname><given-names>Rolf</given-names></name><address><phone>++49-9131-85-26031</phone><email>rolf.buslei@uk-erlangen.de</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><label></label>Departments of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany</aff><aff id="Aff2"><label></label>ENDOC Center for Endocrine Tumors, Hamburg & University of Duisburg-Essen, Essen, Germany</aff><aff id="Aff3"><label></label>Departments of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany</aff><aff id="Aff4"><label></label>Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany</aff><aff id="Aff5"><label></label>Departments of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany</aff><aff id="Aff6"><label></label>Department of Neuropathology, Klinikum Bremen Mitte, Bremen, Germany</aff><aff id="Aff7"><label></label>Department of Neurosurgery, Johannes Wesling Hospital Minden, Minden, Germany</aff><aff id="Aff8"><label></label>Department of Pathology, Ruhr University Bochum, Bochum, Germany</aff><aff id="Aff9"><label></label>Departments of Neuropathology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</aff></contrib-group><pub-date pub-type="epub"><day>19</day><month>8</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>19</day><month>8</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>3</volume><elocation-id>50</elocation-id><history><date date-type="received"><day>4</day><month>8</month><year>2015</year></date><date date-type="accepted"><day>6</day><month>8</month><year>2015</year></date></history><permissions><copyright-statement>© Miermeister et al. 2015</copyright-statement><license license-type="OpenAccess"><license-p><bold> Open Access</bold> This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Introduction</title><p>The term <italic>atypical pituitary adenoma</italic> (APA) was revised in the 2004 World Health Organization (WHO) classification of pituitary tumors. However, two of the four parameters required for the diagnosis of APAs were formulated rather vaguely (i.e., <italic>“extensive”</italic> nuclear staining for p53; <italic>“elevated”</italic> mitotic index). Based on a case-control study using a representative cohort of typical pituitary adenomas and APAs selected from the German Pituitary Tumor Registry, we aimed to obtain reliable cut-off values for both p53 and the mitotic index. In addition, we analyzed the impact of all four individual parameters (invasiveness, Ki67-index, p53, mitotic index) on the selectivity for differentiating both adenoma subtypes.</p></sec><sec><title>Methods</title><p>Of the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis.</p></sec><sec><title>Results</title><p>We determined significant threshold values for p53 (≥2 %; AUC: 0.94) and the mitotic index (≥2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index ≥ 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (<italic>p</italic> < 0.001); OR 5.2// p53 (<italic>p</italic> < 0.001); OR 3.1// mitotic index (<italic>p</italic> < 0.001); OR 2.1// invasiveness (<italic>p</italic> < 0.001); OR 8.2)) were significant for the group of APAs. Furthermore, we describe the presence of nucleoli as a new favorable parameter for TPAs (<italic>p</italic> = 0.008; OR: 0.4; CI95 %: 0.18; 0.77).</p></sec><sec><title>Conclusions</title><p>Here we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s40478-015-0229-8) contains supplementary material, which is available to authorized users.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2015</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>Allemagne</li></country><region><li>Basse-Saxe</li><li>Bavière</li><li>Brême (Land)</li><li>District de Moyenne-Franconie</li><li>Hambourg</li></region><settlement><li>Brême</li><li>Erlangen</li><li>Hambourg</li><li>Hanovre</li></settlement></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Miermeister, Christian P" sort="Miermeister, Christian P" uniqKey="Miermeister C" first="Christian P." last="Miermeister">Christian P. Miermeister</name></region><name sortKey="Bergmann, Markus" sort="Bergmann, Markus" uniqKey="Bergmann M" first="Markus" last="Bergmann">Markus Bergmann</name><name sortKey="Buchfelder, Michael" sort="Buchfelder, Michael" uniqKey="Buchfelder M" first="Michael" last="Buchfelder">Michael Buchfelder</name><name sortKey="Buslei, Rolf" sort="Buslei, Rolf" uniqKey="Buslei R" first="Rolf" last="Buslei">Rolf Buslei</name><name sortKey="Fahlbusch, Rudolf" sort="Fahlbusch, Rudolf" uniqKey="Fahlbusch R" first="Rudolf" last="Fahlbusch">Rudolf Fahlbusch</name><name sortKey="Flitsch, Jorg" sort="Flitsch, Jorg" uniqKey="Flitsch J" first="Jörg" last="Flitsch">Jörg Flitsch</name><name sortKey="Hans, Volkmar H" sort="Hans, Volkmar H" uniqKey="Hans V" first="Volkmar H." last="Hans">Volkmar H. Hans</name><name sortKey="Holsken, Annett" sort="Holsken, Annett" uniqKey="Holsken A" first="Annett" last="Hölsken">Annett Hölsken</name><name sortKey="Knappe, Hans Ulrich" sort="Knappe, Hans Ulrich" uniqKey="Knappe H" first="Hans Ulrich" last="Knappe">Hans Ulrich Knappe</name><name sortKey="Ludecke, Dieter K" sort="Ludecke, Dieter K" uniqKey="Ludecke D" first="Dieter K." last="Lüdecke">Dieter K. Lüdecke</name><name sortKey="Petersenn, Stephan" sort="Petersenn, Stephan" uniqKey="Petersenn S" first="Stephan" last="Petersenn">Stephan Petersenn</name><name sortKey="Saeger, Wolfgang" sort="Saeger, Wolfgang" uniqKey="Saeger W" first="Wolfgang" last="Saeger">Wolfgang Saeger</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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