Årsmøte og kurs. Den norske patologforening. Bergen mars HELSE BERGEN Haukeland universitetssjukehus

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1 Årsmøte og kurs Den norske patologforening Bergen mars 2012 HELSE BERGEN Haukeland universitetssjukehus 1

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3 Innholdsfortegnelse Program 4 Faglige foredrag 9 Postere 29 Påskeegg 37 Deltakerliste 49 3

4 Program Scandic Bergen City mars Fredag 9. mars Registrering Velkommen Faglige foredrag 1. Implementation of step sectioning in the examination of sentinel lymph nodes to improve the detection of micrometastases in breast cancer patients M Valla, PG Mjønes, S Knopp 2. Activation of EGFR mediates invasion of human glioblastoma in vivo KM Talasila, A Soentgerath, P Euskirchen, GV Rosland, J Wang, PC Huszthy, L Prestegarden, KO Skaftnesmo, N Brekka, I Moen, J Nigro, O Vintermyr, M Lund-Johansen, S Mørk, PØ Enger, R Bjerkvig, H Miletic 3. Resultat av 1. års testing for EGFR mutasjoner ved ikke-småcellet lungekarsinom i Norge. Utgår fra Translasjonsgruppen i Norsk LungeCancerGruppe P Jebsen Jubileumsforedrag: Gades Institutt 100 år Professor Ole Didrik Lærum Pause og posterpresentasjon / besøk utstillere (oral presentasjon ved utstillere første 10 min) Gjesteforelesning Lunsj The role of the pathologist in the era of personalized medicine Giuseppe Viale, MD PhD, European Institute of Oncology, Milano, Italia (Foredrag 40 min med etterfølgende diskusjon 20 min) 4

5 Program Scandic Bergen City mars Faglige foredrag 4. IgG4-related sclerosing disease: A new disease entity or a surrogate marker of several diseases? HM Reims, TJ Eide 5. Reestablishing Surgical Pathology Service in Kumasi, Ghana H Stalsberg 6. Primary screening with HPV mrna test in cervical cancer prevention SW Sorbye, S Fismen, T Gutteberg, ES Mortensen, FE Skjeldestad 7. Transcription factors SNAI1, Slug, Twist and FOXC2 regulating Epithelial-Mesenchymal Transition are markers of aggressive human prostate cancer K Gravdal, OJ Halvorsen, SA Haukaas, LA Akslen Kort pause med posterpresentasjon/besøk utstillere Årsmøte DNP (se egen innkalling og saksliste) Festmiddag Lørdag 10. mars Faglige foredrag 8. Estrogen receptor α loss in endometrial carcinoma is linked to epithelial-to-mesenchymal transition and a potential for PI3Kinase inhibition E Wik, MB Ræder, C Krakstad, J Trovik, E Birkeland, H Werner, M Mannelquist, I Stefansson, AM Oyan, KH Kalland, LA Akslen, HB Salvesen 9. Nytt placentaklassifikasjonssystem pioner i gammelt terreng G Turowski, B Roald 10. Smooth muscle in the human mitral valve IS Nordrum, B Skallerud 5

6 Program Scandic Bergen City mars Påskeegg Påskeegg 1- Nguyen Tan Dat Påskeegg 2- Christina Vogt Pause med posterpresentasjon/besøk utstillere Fortsettelse påskeegg /faglige foredrag Påskeegg 3- G. Cecilie Alfsen Påskeegg 4- Anna Margrét Jónsdóttir Påskeegg 5- Sura Aziz Faglig foredrag 11. Betydningen av redusert telomerlengde for kreftutvikling ved langvarig ulcerøs kolitt M Friis-Ottessen, L Bendix, PM De Angelis, OP F Clausen Kort pause Faglige foredrag 12. Hvordan selektere de riktige dødsfall for obduksjon? GC Alfsen Prisutdeling Lunsj Klassifikasjon av VIN-lesjoner års trend mht cytologisk atypi ved SUS J Berland 6

7 Program Scandic Bergen City mars POSTERE: Dissection of the vertebral artery in an infant S Kristoffersen Axl and VE-cadherin expression as markers of angiogenesis in human breast cancers KA Veien, K Krüger, IM Stefansson, JB Arnes, K Collett, LA Akslen Quality assessment of the registration of vulvar and vaginal premalignant lesions at the Cancer Registry of Norway E Enerly, F Bray, C Mellem, BT Hansen, G Kjølberg, T Dahl, TB Johannesen, M Nygård Analysis of GNAQ mutations in subtypes of malignant melanoma HE Puntervoll, E Vuhahula, A Molven, LA Akslen Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer K Krüger, IM Stefansson, K Collett, JB Arnes, T Aas, LA Akslen Prognostic and predictive biomarkers from the stroma of head and neck cancer DE Costea, A Hills, G Kalna, J Thurlow, AC Johannessen, M Partridge 7

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9 Abstract 1 Implementation of step sectioning in the examination of sentinel lymph nodes to improve the detection of micrometastases in breast cancer patients Valla M, Mjønes PG, Knopp S, avd for patologi og medisinsk genetikk, St. Olavs Hospital Objective To examine whether a new protocol for examination of sentinel lymph nodes (SLNs) would lead to the detection of more metastases. Background Sections of 1 mm would identify most SLN macrometastases, and step sections at intervals of μm would identify most micrometastases. Methods 111 breast cancer patients who underwent the SLN procedure at St. Olavs Hospital in Trondheim, Norway in 2008 were included in the study group. Their SLNs were processed according to a new standardized protocol with sections of 2-3 mm being step sectioned at intervals of μm. 109 breast cancer patients undergoing the SLN procedure in 2007 were used as a reference group. Results Metastases were found in 29% of the cases, compared to 26% in the reference group. Step sectioning of SLNs revealed metastases in five cases initially found to be negative. The metastases of the study group were smaller, with a median value of 1.25 mm compared to 4.25 mm in the reference group. Conclusion Step sectioning led to the detection of metastases in SLNs initially found to be negative. The median size of the metastases was considerably smaller in the study group than in the reference group 9

10 Abstract 2 Activation of EGFR mediates invasion of human glioblastoma in vivo. Krishna M. Talasila 1, Anke Soentgerath 1, Philipp Euskirchen 1, Gro V. Rosland 1, Jian Wang 1, Peter C. Huszthy 1, Lars Prestegarden 1, Kai Ove Skaftnesmo 1, Narve Brekka 1, Ingrid Moen 1, Janice Nigro 1, Olav Vintermyr 4, Morten Lund-Johansen 2,3, Sverre Mørk 4, Per Øyvind Enger 1,2, Rolf Bjerkvig 1,5 & Hrvoje Miletic 1,4 1 Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway 2 Department of Neurosurgery, Haukeland University Hospital, 5021 Bergen, Norway 3 Institute of Surgical Science, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway 4 Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway 5 NorLux Neuro-Oncology Laboratory, CRP-Santé, Luxembourg Human glioblastoma is the most frequent and most malignant primary brain tumor. Molecular therapies that target angiogenesis or important growth factor receptors have shown response in some cancer types, however, were not effective in clinical trials of brain cancer. To understand therapy resistance, we have developed a unique animal model for human glioblastoma that demonstrates invasion and angiogenesis, essential features of glioblastoma growth. To investigate general mechanisms of invasion and angiogenesis, we analyzed angiogenic and invasive tumor phenotypes in our animal model by histology, immunohistochemistry and array CGH. We could show that only glioblastoma with EGFR amplification grow as highly invasive and non-angiogenic lesions. In contrast, non-amplified tumors are less invasive, have an early onset of angiogenesis and express high levels of angiogenic factors. Interestingly, high EGFR amplification was detectable in virtually all tumor cells of the invasive phenotype while corresponding patient tumors showed areas with high, low or not detectable EGFR amplification, suggesting a selection towards highly amplified tumor cells in the xenografts. As our animal model might reflect the development and progression of EGFR amplified tumors in patients, we analyzed a tissue microarray of 206 patients for EGFR amplification, expression and activation to reveal whether we might find the same pattern in invasive/nonangiogenic versus angiogenic tumor areas. Interestingly, the only factor which correlated to invasive/non-angiogenic tumor growth was activation (phosphorylation) of EGFR. 10

11 To functionally verify the role of EGFR activation in invasion, we overexpressed a dominant negative EGFR in amplified xenograft tumors to block EGFR activity. These modified tumors switched to an angiogenic phenotype which was accompanied by upregulation of HIF1A and VEGF and downregulation of Src/FAK, a downstream signaling pathway of EGFR involved in migration. Taken together, this study shows that brain tumors can escape towards angiogenic tumor growth when invasion is inhibited; for a successful therapy the targeting of major pathways involved in both, invasion and angiogenesis, might be necessary. 11

12 Abstract 3 Resultat av 1. års testing for EGFR mutasjoner ved ikke-småcellet lungekarsinom i Norge. Utgår fra Norsk Lunge Cancer Gruppes Translasjonsgruppe. Peter Jebsen Fra 1. mai 2010 til 30 april 2011 er 1058 pasientprøver analysert, 470 prøver ved OUS, 277 i Bergen, 191 i Trondheim og 120 i Tromsø. Omtrent halvparten av dem som fikk diagnosen ikke-småcellet lungekarsinom i Norge har fått utført EGFR-test i perioden. Svartid har tidlig i perioden vært relativt lang, men er nå 7-10 virkedager, hvilket anses adekvat. EGFR mutasjonsrate varierer fra 7,5% til 14,1% mellom laboratoriene (ikke signifikant). Nasjonal mutasjonsrate etter 1 år var 11,6%, noe høyere for adenokarsinom. Mutasjonsrate i plateepitelkarsinom var 3%. Mutasjonsraten hos kvinner er nesten 3 ganger så høy som hos menn (17,6% vs 6,3%). Forskjellen skyldes neppe forskjell i røykevaner hos menn og kvinner men antas å ha ukjent kjønnsspesifikk forklaring. Hos mange pasienter finnes kun cytologisk prøvemateriale tilgjengelig. Av 80 cytologiske prøver (7,6% av prøvene) var 9 (11,3%) positive dvs omtrent samme egfr-mutasjonsfrekvens som i biopsimateralet. Norsk Lunge Cancer Gruppe anbefaler fortsatt videreføring av mutasjonstesting av alle pasienter med ikke-småcellet lungekreft. 12

13 Abstract 4 IgG4-related sclerosing disease: A new disease entity or a surrogate marker of several diseases? HM Reims and TJ Eide, Department of Pathology, Oslo University Hospital, Rikshospitalet. Background: An increased serum level of immunoglobulin G4 (IgG4), the least abundant of the four subclasses of IgG, is a marker of the recently recognized IgG4-related sclerosing (or systemic) disease (ISD). The disease usually presents as a tumor-like condition, histologically characterized by lymphoplasmocytic infiltrates with abundant IgG4-positive plasma cells, and often with sclerosing fibrosis. The syndrome predominantly affects middle-aged and elderly men. High serum IgG4 concentrations were first demonstrated in 2001 in patients with sclerosing pancreatitis. There has been a marked increase in the number of publications on the condition during the last 3-5 years. An important clinical aspect of the condition is that patients often respond well to glucocorticoid therapy. Objective: The aim of this presentation is to give an overview of the many organ manifestations of ISD, which is apparently underdiagnosed and still little known among clinicians and pathologists. Clinically, ISD can give rise to suspicion of a tumor, whereas for the pathologist, the condition may appear as a non-specific inflammatory lesion with fibrosis and mucosal ulceration in hollow organs. A definite diagnosis requires immunohistochemical demonstration of an increased number of IgG4-positive plasma cells. Results: During the last two years, we have evaluated a number of cases in our department, with unclear conditions affecting different organs (pancreas, biliary tract, gastrointestinal tract, aorta, kidneys, retroperitoneum, etc.), and often with clinical suspicion of a tumor. These have manifested histologically as a fibrosing (and sometimes ulcerating) inflammatory condition. In many cases, immunohistochemical staining for IgG and IgG4 has shown increased numbers if IgG4-positive plasma cells in the tissue, and some cases have been diagnosed as ISD. Discussion: Many aspects of ISD still remain to be clarified, regarding the etiology, the pathogenesis, the prevalence and in particular diagnostic criteria. For the pathologist, it is important to be aware of the condition and to be able to apply immunohistochemistry for the demonstration of IgG and IgG4. However, in some cases an increased amount of IgG4 can also be found in patients without ISD. It is therefore important that the diagnosis is used with caution, and only when other conditions are unlikely. 13

14 Abstract 5 Reestablishing Surgical Pathology Service in Kumasi, Ghana: Helge Stalsberg, Universitetssykehuset I Nord-Norge In 2005, Ghana had 5 active surgical pathologists and a population of 22 million. At Komfo Anokye Teaching Hospital (KATH) in Kumasi, all histology stopped in April Reasons were a broken microtome, low budget priority, the single pathologist overloaded with teaching and forensic autopsy commitments. The department lost accreditation to train pathologists. The head of KATH oncology department met the author during a conference and asked for help. At a planning visit to KATH, a comprehensive plan was worked out. KATH administration acquired basic new equipment. Two KATH technicians trained at University Hospital of North Norway (UNN) for 3 months. On their return, slides were produced at KATH and sent to UNN for diagnosis. Two young doctors from KATH were trained in pathology at UNN for 4 years. Three double-headed microscopes and one 6-headed conference microscope were provided from Norway. Immunohistochemistry was established at KATH in A 3- month introductory training of two Ghanaian medical technologists in Pap-smear screening will be given in Attracted by ongoing activity, a senior histotechnologist and three Ghanaian pathologists were recruited to KATH in The two pathologists trained at UNN returned to KATH in 2010 and were joined by a Nigerian pathologist in By the end of 2010, KATH Pathology department was serving the needs of the KATH clinical departments and a few outside hospitals. In 2010, the department reported on 5600 surgical specimens and 300 FNACs. Accreditation to train pathologists is still pending. Financial support for the project was given by both hospitals and the Norwegian Government (The Norwegian Agency for Development Cooperation, NORAD). Important success factors have been: Appreciation of the importance of pathology by KATH and their initiative to ask for help, personal contact and commitment, support from both hospitals and NORAD, and a comprehensive plan for sustainable development with attention to the needs and wishes of the receiving institution. 14

15 Abstract 6 Primary screening with HPV mrna test in cervical cancer prevention Sorbye SW 1, Fismen S 1, Gutteberg T 2,3, Mortensen ES 1,3 and Skjeldestad FE 4 1 Department of Pathology, University Hospital of North Norway, 2 Department of Microbiology and Infection Control, University Hospital of North Norway and 3 Institute of Medical Biology, 4 Institute of Clinical Medicine; University of Tromso, Norway. Aims. Primary cervical screening using HPV test relative cytology has been advocated because of higher sensitivity for detection of CIN2+. However, HPV DNA testing is not costeffective in women years due to a high positivity rate of HPV infection. The objective was to assess the performance of HPV mrna test in primary screening. Methods. In women were tested with HPV mrna (PreTect HPV-Proofer) in primary and secondary screening. Women with a history of abnormal PAP-smear, with biopsy with CIN2+ before screening or until 3 months after, were excluded. Eligible were women years in a situation resembling primary screening. Follow-up through December 2009 were done through national surveillance of CIN2+ in three registries administered by the Norwegian Cancer Registry (CIN treatment registry, CIN biopsy registry, Cancer registry). All analyses were done by survival analysis in SPSS. Results. 5.2% were HPV mrna positive at screening. The overall cumulative rate of CIN2+ was 1.8% through 81 months of follow-up. For women years (n=5 085) 9.4% were HPV mrna positive at baseline and the overall cumulative rate of CIN2+ was 2.9%. For women years (n=7 873) 2.5% were HPV mrna positive at baseline and the overall cumulative rate of CIN2+ was 1.1%. Cumulative rates by baseline status for HPV mrna positive and HPV mrna negative in women years were 20.7% and 1.0%, respective 20.1% and 0.6% in women aged years. Except for HPV-18, the cumulative incidence rates for CIN2+ were relative constant for HPV-16 and HPV-31,-33,-45 by age. Conclusion. The HPV mrna test can be used in primary screening for both women and years. Due to differences in test properties and understanding of oncogenesis of 15

16 cervical cancer, studies comparing head-to-head DNA and mrna tests in primary screening are warranted. 16

17 Abstract 7 Transcription factors SNAI1, Slug, Twist and FOXC2 regulating Epithelial- Mesenchymal Transition are markers of aggressive human prostate cancer. Karsten Gravdal, 1 Ole J. Halvorsen, 1 Svein A. Haukaas, 2 Lars A. Akslen 1 1 The Gade Institute, Section for Pathology, University of Bergen, Haukeland University Hospital, Bergen, Norway 2 Department of Surgical Sciences, University of Bergen, Haukeland University Hospital, Bergen, Norway PURPOSE: In carcinomas, Epithelial-Mesenchymal Transition (EMT) gives rise to invasive fibroblastoid tumor cells, and this study evaluates expression of selected transcription factors (TF) in different human prostatic tissues with focus on EMT, angiogenesis and followup information. EXPERIMENTAL DESIGN: Paraffin sections from 104 radical prostatectomies with long follow-up, 33 castration resistant prostate cancers (CRPCs), 28 non-skeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias (BPH) were immunohistochemically stained for SNAI1, Slug, Twist, FOXC2, E-cadherin and N-cadherin. MAIN RESULTS: Localized prostate carcinomas were characterized by presence of an E- cadherin to N-cadherin switch (EN-switch) being associated with strong SNAI1 (P = 0.013), and SNAI1 accentuated at the tumor stromal border, SNAI1-SB (P = 0.029). Strong Twist was significantly associated with strong nuclear expression of HIF-1α in both localized prostate cancer (P = 0.025) and CRPC (P = 0.049). SNAI1-SB (P = 0.030) and Twist (P = 0.042) were also associated with increased vascular proliferation. In univariate survival analyses, strong Slug (P = 0.003) and Twist (P = 0.033) were the only TFs significantly related to reduced cancer specific survival, and in multivariate analysis, both strong Twist (HR, 2.4; P = 0.032) and strong Slug (HR, 3.2; P = 0.003) were independent predictors of clinical recurrence. CONCLUSION: The EN-switch, a hallmark of EMT, was most prevalent among localized prostate cancers and was significantly related to the E-cadherin gene repressor SNAI1. As a novel finding, Twist was associated with HIF-1α in both localized PC and CRPC, and both Twist and SNAI1-SB were related to vascular proliferation, suggesting EMT and angiogenesis to be co-regulated and driven by hypoxia. Twist and Slug were related to 17

18 reduced patient survival, and both were independent predictors of clinical recurrence, suggesting a pivotal role for Twist and Slug in metastatic progression to death from prostate cancer. These findings could have significant effect on the future treatment of prostate cancer patients, where tailored therapy should be directed against both angiogenesis and EMT. 18

19 Abstract 8 Estrogen receptor α loss in endometrial carcinoma is linked to epithelial-tomesenchymal transition and a potential for PI3Kinase inhibition. Elisabeth WIK, MD 1,2, Maria B. RÆDER, MD, PhD 1,2, Camilla KRAKSTAD, PhD 1,2, Jone TROVIK, MD 1,2, Even BIRKELAND, MSc 1,2, Henrica M.J. WERNER, MD 1,2, Monica MANNELQVIST, PhD 3, Ingunn M. STEFANSSON, MD, PhD 3,4, Anne M. OYAN, PhD 5,6, Karl H. KALLAND, MD, PhD 5,6, Lars A. AKSLEN, MD, PhD 3,4, Helga B. SALVESEN, MD, PhD 1,2 Purpose: We hypothesized that ERα loss, associated with poor prognosis in endometrial carcinomas, is reflected in transcriptional signatures defining the molecular basis for tumor phenotype and targets for new therapy. Patients and methods: Endometrial carcinoma samples in a primary investigation cohort (n=76) and three independent validation cohorts (n=155/286/111) were analyzed. Biomarkers were assessed by IHC, DNA oligonucleotide microarray or qpcr in the cohorts, annotated for comprehensive histopathologic- and clinical data, including follow-up. Results: ERα protein expression was highly correlated with mrna expression of the receptor gene (ESR1), high FIGO stage, non-endometrioid histology, high histologic grade and poor survival (all P<0.001). ERα was significantly associated with the same variables also in subgroup analyses comprising only endometrioid cases and endometrioid/grade ½ tumors. In the investigation cohort, activation of genes involved in Wnt-, Sonic hedgehog- and TGF-β signaling, were highly associated with loss of ERα (P< 0.001), indicating potential EMT activation in this group of tumors. Transcription factors cross-linking with TGF-β were activated in the ERα negative tumors in an EMT promoting way. An association between receptor loss and activation of EMT was further found in independent data sets. We generated an EMT mrna signature and found also this associated with ERα loss (P<0.001). The signature had stronger independent prognostic impact in multivariate Cox survival analyses compared to single EMT markers ((HR=1.4; 95% CI: , P=0.005). Furthermore, PI3Kinase- and mtor inhibitors were amongst the top ranked drugs with signatures anticorrelated with the signature for ERα loss. PI3K activation, measured through a PI3Kinase signature and high expression of the PI3Kinase surrogate marker Stathmin, was correlated to 19

20 ERα loss, (P<0.001 and P=0.03, respectively). High expression of Stathmin was also associated with a panel of EMT markers. Conclusion: Integrated genomic profiling of endometrial carcinomas associates ERα loss with epithelial-to-mesenchymal transition and activation of PI3Kinase signaling, supporting a potential for PI3Kinase-, mtor- and EMT inhibitors in metastatic ERα negative endometrial carcinomas. The present study supports that ERα status should be integrated systematically in trials tailoring surgical and systemic therapies in endometrial cancer. 20

21 Abstract 9 Nytt placenta klassifikasjonssystem pioner i gammelt terreng Gitta Turowski, overlege og stipendiat, Oslo Universitetssykehus-Ullevål, Senter for Barne og Svangerskapsrelatert patologi. Borghild Roald, professor og overlege, Oslo Universitetssykehus-Ullevål, Senter for Barne og Svangerskapsrelatert patologi. Per i dag finnes det ingen internasjonal akseptert, klinisk lett forståelig, morfologisk placenta klassifikasjon. Dette gjør registrering, rapportering og sammenligning av placentadiagnoser nasjonalt og internasjonalt vanskelig. Store fremskritt innen basalforskning relatert trofoblastfunksjon og placentainsuffisiens de siste tiår har resultert i bedre forståelse av placentas funksjon og dysfunksjon. Metode: Vi har konstruert et klinisk orientert, forenkelt klassifikasjonssystem med diagnoser relatert til patologiske prosesser, basert på delvis modifiserte internasjonalt publisert og aksepterte kriterier av makroskopiske og mikroskopiske funn i placenta. Diagnose kategori Diagnostisk ordlyd 1. Normal placenta 2. Placenta med chorioamnionitt 3. Placenta med villitt (inkl.vue = villitt av ukjent etiologi) 4. Placenta med maternoplacentær sirkulasjonsforstyrrelse 5. Placenta med føtoplacentær sirkulasjonsforstyrrelse 6. Placenta med modningsfeil 7. Placenta med funn forenlig med genetisk feilutvikling 8. Placenta med implantasjonsfeil 9. Annet Algoritmen ved fastsetting av hoveddiagnoser er som ved en obduksjon. I tillegg til en standardisert hoveddiagnose blir ytterligere funn eller klinisk relevante observasjoner diskutert i et kommentar/vurderingsfelt. Vi har testet brukervennligheten og forståelsen av det nye klassifikasjonssystemet i placenta diagnostikk i vårt sykehus i mer enn to år. Vi har dessuten testet reproduserbarheten av kriteriene på et klinisk godt identifisert placenta materiale fra 332 dødfødte barn og 31 normale kontroller. 21

22 Resultater og konklusjon: Klassifikasjonen er lett å bruke for patologer, med høy interobserver korrelasjon. Probleme og diskrepans er hovedsakelig knyttet til modningsforstyrrelser og gradering av maternoplacentære sirkulasjonsforandringer. Utfordringene er også knyttet til balansen mellom hoveddiagnose og ytterligere funn. Tilbakemeldingene fra klinisk miljø er meget gode. 22

23 Abstract 10 Smooth muscle in the human mitral valve Nordrum IS, Skallerud B The mitral valve is increasingly been regarded as having dynamic and contractile capabilities, but the presence of muscle in the valve have been investigated to a limited extent. The aim of this study was to investigate the presence, architecture and phenotype of muscle in the human mitral valve. Twelve mitral valves were cut into strips, sectioned for histology, and the cut edges examined by microscope after staining included immunophenotyping. Smooth muscle bundles were present at the atrial side of the leaflets, and distinctly more in the anterior leaflet than in the posterior leaflet. The smooth muscle bundles extended up to two thirds the distance from the annulus to the rim of the leaflets, and they ran in various directions but seemingly mainly perpendicular to the annulus. The thickness and density of the bundles seemed to decrease with the distance from the annulus, and also in a radial direction from the centre portion of each leaflets attachment at the annulus towards the rim. Cross striation was not detected. Cardiac muscle in the left atrial wall extended into the annular base of the leaflets in close proximity to the annular border of the smooth muscle bundles in the leaflets. In conclusion, especially the anterior leaflet of the mitral valve seems to have a separate smooth muscle formed as a meshwork of bundles close to the atrial surface. Muscle fibers in the human mitral valve: extent of smooth muscle and implications for dynamic modelling. Accepted APMIS

24 Abstract 11 Betydningen av redusert telomerlengde for kreftutvikling ved langvarig ulcerøs kolitt. Mariann Friis-Ottessen 1, Laila Bendix 2, Paula M. De Angelis 1 and Ole Petter F. Clausen 1,3 1 Avdeling for Patologi, klinikk for Diagnostikk og Intervensjon, Oslo Universitetssykehus, Rikshospitalet, 2 Institut for Folkesundhedsvidenskab, Afdeling for Social Medicin, Københavns Universitet, 3 Avdeling for Patologi, Universitetet i Oslo. Det er vist at pasienter med ulcerøs kolitt har kortere telomerer i tykktarmsslimhinnen enn normalt. Korte telomerer er knyttet til kromosominstabilitet og DNA-aneuploidi som er uavhengige risikofaktorer for utvikling av dysplasi. Det er antatt at ikke bare generelt redusert telomerlengde, men også antall ultrakorte telomerer, er viktig for utvikling av kromosominstabilitet. Vi har derfor undersøkt både generell telomerlengde og mengden ultrakorte telomerer, samt kvantitert telomerase i forskjellige forstadier for kreft ved langvarig ulcerøs kolitt (>10 års sykdomsvarighet). Resultatene er korrelert til dysplasi og aneuploidi. Material og metoder: Vi har undersøkt 13 kolektomipreparater fra pasienter med ulcerøs kolitt, og analysert åtte lesjoner langs hver colon. Kolektomiene er kategorisert som non-progressorer, dvs. uten dysplasi og aneuploidi og progressorer, med minst ett område med aneuploidi eller dysplasi. Generell telomerlengde er undersøkt ved kvantitativ PCR, og mengden ultrakorte telomerer er målt med en relativt ny metode kalt Universal STELA. Sistnevnte metode er PCR-basert og muliggjør kvantitering av de korteste telomerene i en prøve. Metoden visualiseres ved Southern Blot. Ekspresjon av telomerase ble analysert ved immunhistokjemi og angitt i prosent. Resultater: Vi finner en signifikant forskjell i telomerlengde i dysplastiske og ikke-dysplastiske områder i lesjoner fra alle 13 tarmer. Dysplastiske områder har signifikant kortere telomerlengde, samt signifikant flere ultrakorte telomerer enn ikke-dysplastiske områder. Når det gjelder ploidistatus har vi ikke funnet signifikant forskjell i telomerlengde mellom diploide områder 24

25 og områder med aneuploidi. Det er signifikant høyere ekspresjon av telomerase i diploide områder enn i områder med aneuploidi, men ingen forskjell mellom dysplastiske og ikkedysplastiske lesjoner. Progressor-tarmer har flere ultrakorte telomerer enn non-progressor tarmer. Innen progressor-tarmene har områdene med dysplasi generelt kortere telomerer samt flere ultrakorte telomerer enn ikke-dysplastiske områder. Konklusjon: Vi har konfirmert betydningen av korte telomerer for kreftutviklingen ved ulcerøs kolitt, og vist at tumorprogresjon er assosiert med både generell telomerforkortning og antall ultrakorte telomerer. Telomerforkortningen ser ut til å være knyttet til dysplasiutviklingen, uten at vi kunne finne assosiasjon til ploidistatus. Funnet av mindre telomerase i aneuploide områder kan tyde på at telomerlengde likevel er assosiert med utvikling av aneuploidi. 25

26 Abstract 12 Hvordan selektere de riktige dødsfall for obduksjon? G. Cecilie Alfsen, Avdeling for patologi, Akershus universitetssykehus og Medisinsk fakultet, Oslo universitet. Bakgrunn: Synkende obduksjonstall gjør en målrettet seleksjon nødvendig. En gjennomgang av sykehusobduksjoner i Norge i 2005 har vist at obduksjonsresultatet førte til endring av dødsårsak hos 61 %, med skifte av sykdomsgruppe hos 32 %. 1 Fra 2009 har vi ved Ahus systematisk gått gjennom alle dødsfall og vurdert oppsett og innhold i dødsmeldingene. Erfaringene fra dette arbeidet kan gi retningslinjer mht mulighet for seleksjon av dødsfall for postmortal undersøkelse. Materiale: Det presenteres resultater fra to ulike materialer der dødsmeldinger ble gjennomgått. 1) Dødsfall uten obduksjon i perioden mai 2008 tom desember 2009 (n=1001) og 2) dødsfall med obduksjon i 2009 og 2011 (n=305). For alle kasus ble det vurdert om dødsmelding var korrekt i forhold til korrekt koding ved Dødsårsaksregisteret (DÅR). Ved evt. endring ble nye diagnoser etter endring av dødsmelding (for dødsfall uten obduksjon) eller etter obduksjon registrert. Vurdering av dødsmeldinger ble alltid gjort før evt. obduksjon. Nye dødsmeldinger for kasus uten obduksjon ble registrert ved DÅR, som anga ny dødsårsak som ICD-10 koder. Evt. endring av dødsårsak etter obduksjon ble vurdert manuelt. Resultat: Dødsmeldinger fra ikke-obduserte ble endret for 22 %, med skifte av sykdomsgruppe for 12 %. Obduserte ble skilt i to grupper ut fra om dødsmeldingen ble vurdert som OK eller ikke. Endring av sykdomsgruppe ble funnet hos hhv 24 % og 67 %. En sammenligning av dødsårsaker før og etter obduksjon viste store utskiftninger i alle grupper, men en betydelig reduksjon spesielt for diagnosene sepsis, pneumoni og uspesifiserte tilstander. Gruppene Hjertesykdom av ikke-iskemisk årsak og Cerebrovaskulære sykdommer viste spesielt dårlig korrelasjon mellom premortal vurdering ved dødsmelding og obduksjonsresultat. Færrest endringer ble funnet ved aneurysmedødsfall og ved kjente kreftdødsfall, men antall nye krefttilfeller som underliggende dødsårsak økte likevel med 17 % etter obduksjonen. Konklusjon: 1 Alfsen GC, Mæhlen J. Obduksjonens betydning for registrering av dødsårsak. Tidsskr Nor Legeforen 132: ,

27 Patologens gjennomgang av dødsfall med vurdering av dødsmelding og sykehistorie kan sannsynligvis bidra til bedre seleksjon av kasus til obduksjon. Seleksjon til obduksjon ut fra sykdomsgrupper er problematisk. Institusjoner bør sette opp minimumskriterier for når obduksjon skal tilstrebes og målrette obduksjonsvirksomheten hvis undersøkelsen skal fungere hensiktsmessig som kvalitetskontroll. 27

28 Abstract 13 Klassifikasjon av VIN-lesjoner og 10 års trend mht cytologisk atypi ved SUS. Jannicke Berland, Stavanger universitetssykehus. Gyn-onkologisk håndbok er under revidering og vil få et nytt avsnitt om preneoplasi/ VINlesjoner, som er av 2 ulike typer/ etiologier. Presenteres kort. Patologiske diagnoser bør være spesifikke, men materialet i cytologi tillater ikke alltid dette. Noen data fra søk i databasen ved Avdeling for patologi ved SUS for perioden presenteres mht diagnosekodene M69000 (sannsynlig benign), M69700 (usikker benign/ malign) og M69760 (malignitetsuspekt), med utviklingstrekk og noen analyser. 28

29 Abstract poster 1 Dissection of the vertebral artery in an infant Stine Kristoffersen, Haukeland Universitetssykehus Spontaneous subarachnoid haemorrhage (SAH) in infants is uncommon, but is sometimes seen after rupture of aneurysms, and in different disorders. Traumatic SAH is common after serious accidental head injury, but is also reported after child abuse with vigorous shaking. To avoid unnecessary accusations of innocent care givers, it is important not to misinterpret the findings as abusive head trauma with SAH in small children. In the presented case, a nearly two-year-old girl was brought to the hospital after a fall witnessed by her father. The girl was unconscious, with elevated intracranial pressure, SAH and bilateral retinal haemorrhage (RH). She was pronounced dead after nine hours. Pre mortem angiography revealed a dissection of the right vertebral artery, and post mortem examination revealed a traumatic lesion deep in the neck, at the base of the skull. No characteristics of shaking were found, and there were no visible external lesions. Based on the radiological and post mortem findings, we believe that an accidental fall caused a blunt force trauma with a subsequent dissection of the right vertebral artery, leading to SAH. To our knowledge, accidental tear of one of the vertebral arteries, leading to SAH in an infant, has previously not been described. Child abuse is an important exclusion diagnosis with serious legal implications. 29

30 Abstract poster 2 Axl and VE-cadherin expression as markers of angiogenesis in human breast cancers Kristi Anne Veien, 1 Kristi Krüger, 1 Ingunn M. Stefansson, 1,2 Jarle B. Arnes, 1,2 Karin Collett, 2 Lars A. Akslen 1,2 1 The Gade Institute, Section for Pathology, University of Bergen, Norway 2 Department of Pathology, Haukeland University Hospital, Norway Background: The aim of our study was to investigate vascular expression of Axl and VEcadherin as potential markers of angiogenesis in human breast carcinoma. Materials and methods: Immunohistochemical staining was performed using antibodies against Axl and VE-cadherin. Expression was examined in a population-based series of breast cancers collected in Hordaland County (Norway) during The series is a nested case-control study as part of the Norwegian Breast Cancer Screening Program, and consists of 95 invasive interval cancers and 95 invasive screen detected cancers matched by tumor diameter. Positive microvessels were counted in 10 consecutive high power fields within hotspot areas according to previously established criteria and expressed as microvessel density (MVD) by mean number of microvessels per mm 2. Results: The MVD for Axl was associated with progesterone receptor status (p=0.026), HER- 2 status (p=0.030) and basal-like phenotypes: CK5/6+ P-cadherin+ (p=0.009), ER- HER2- CK5/6+ (p=0.014) and ER- HER2- CK5/6+ and/or EGFR+ (p=0.027). In contrast, MVD by VE-cadherin expression (n=127) indicated negative associations with basal-like phenotypes: CK5/6+ or P-cadherin+ or EGFR+ (p=0.034), and ER- HER2- P-cadherin+ (p=0.003). VEcadherin expression also tended to be associated with better patient survival (p=0.067). Conclusion: High MVD by vascular expression of Axl was associated with aggressive features in our breast cancer series, especially the basal-like phenotype, whereas MVD by VE-cadherin expression appeared to be related to less aggressive tumors. 30

31 Abstract poster 3 Quality assessment of the registration of vulvar and vaginal premalignant lesions at the Cancer Registry of Norway Enerly E, Bray F, Mellem C, Hansen BT, Kjølberg G, Dahl T, Johannesen TB, Nygård M. Cancer Registry of Norway, Oslo University Hospital, Post Box 5313 Majorstuen, 0304 Oslo, Norway. Abstract Background: A crucial factor concerning the utility of Cancer Registries is the data quality with respect to comparability, completeness, validity and timeliness. However, the data quality of the registration of premalignant lesions has rarely been addressed. High grade vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) are premalignant lesions which may develop into cancer, and are often associated with infection with the human papillomarvirus (HPV). The aim was to evaluate the quality of registration of VIN and VaIN at the Cancer Registry of Norway (CRN). Material and methods: We re-collected all notifications with high grade VIN and VaIN diagnoses during 2002 to 2007 from pathology laboratories, and compared these to the data in the CRN database so as to quantitatively measure the completeness, validity and timeliness of the data. Results: Over the period 2002 to 2007 we estimated the completeness of the 1556 VIN and 297 VaIN notifications to be 95.0% and 92.9%, respectively. The original and reabstracted topography codes showed major discrepancies for 12 of 642 (1.9%) VIN and 7 of 128 (5.5%) VaIN notifications. The original and reabstracted morphology codes for VIN and VaIN were identical for 724 out of 814 notifications. Sixteen notifications had a major discrepancy. For the period 2002 to 2007 the median time elapsed between date of diagnosis and date of registration were 436 and 441 days for VIN and VaIN cases, respectively. Discussion: Based on the present analysis of the comparability, completeness, validity and timeliness of premalignant lesions of vulva and vagina, we conclude that the Cancer Registry of Norway is able to monitor such premalignant lesions satisfactorily. 31

32 Abstract Poster 4 Analysis of GNAQ mutations in subtypes of malignant melanoma HE Puntervoll 1, E Vuhahula 2, A Molven 1,3 & LA Akslen 1,3 1 The Gade Institute, UiBergen, Norway; 2 Department of Pathology, Muhimbili University College of Health Sciences, Dar es Salaam,Tanzania; 3 Section for Pathology, Haukeland Univ. Hospital, Bergen, Norway Background: The MAP kinase pathway has been implicated in the pathogenesis of cutaneous melanoma, and mutations in BRAF and NRAS are commonly found in subtypes of melanomas as well as in benign nevi. Recently, several publications have reported frequent mutations in codon 209 of GNAQ in blue nevi and uveal melanoma, revealing an alternative path to MAP kinase activation. Aim of study: We wanted to investigate the prevalence of GNAQ mutations in codon 209 in a broad spectre of cutaneous melanoma, previously screened for mutations in BRAF, NRAS and EGFR. Methods: 75 benign and malignant tumors of different subgroups were collected at the Department of Pathology, the Gade Institute, Haukeland University Hospital, including: Spitz nevi, superficial spreading melanoma, superficial spreading melanoma in situ, lentigo malignant melanoma, nodular melanoma, metastases from nodular melanoma and uveal melanoma. Additionally, 14 acral African melanomas were collected at the Department of Pathology, Muhimbili University college of Health Sciences, Dar Es Salaam, Tanzania. Tumor tissue was manually dissected from formalin fixated paraffin-embedded sections, before GNAQ exon 5 was screened for mutations in codon 209 by direct Sanger sequencing. Further sample collection and analysis are ongoing. Results: The sequence analysis detected mutations in codon 209 in all five uveal melanomas tested (four harbored a Q209L mutation, and one had a Q209P mutation). However no mutations were found in any of the other subtypes of malignant melanoma. Conclusion: Our study shows that there appears to be a general lack of GNAQ mutations in cutaneous melanoma. This confirms that there may be different routes to MAP kinase activation in malignant melanoma as suggested by other studies. 32

33 Abstract poster 5 Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer K Krüger 1, IM Stefansson 1,2, K Collett 2, JB Arnes 1,2, T Aas 3, LA Akslen 1,2 1 The Gade Institute, Section for Pathology, University of Bergen N-5021, Norway; 2 Department of Pathology, Haukeland University Hospital, Bergen N-5021, Norway; 3 Department of Surgery, Haukeland University Hospital, Bergen N-5021, Norway Angiogenesis, the formation of new blood vessels from pre-existing ones, is essential in tumour growth and metastasis. Microvessel density (MVD) is the most widely used method for quantification of tumour angiogenesis. We here present a novel angiogenesis marker, microvessel proliferation (MVP) based on a dual immunohistochemical stain of nestin and Ki-67. Nestin is an intermediate filament protein expressed in a variety of undifferentiated cells, including newly synthesized endothelial cells (1-3), and used in this study to stain the vasculature. Proliferating cells were recognized by their Ki-67 positivity, and immature microvessels were recognized by their nestin positivity combined with their morphology. Proliferating microvessels contains endothelial cells co-expressing nestin and Ki-67. Microvessel proliferation was estimated by vascular proliferation index (VPI), the ratio between vessels containing immature proliferating endothelial cells and the total number of immature vessels. VPI was evaluated in 178 breast cancer tissue sections. High VPI showed significant association to several markers of aggressive breast cancer, including negative estrogen receptor (ER) status (p=0.003), high tumour cell proliferation by Ki-67 (p=0.004), high p53 expression (p=0.001), five immunohistochemical profiles for the basal-like phenotype (odds ratios (OR); range ), and the triple negative phenotype (TNP)(p=0.040). Concerning the mode of detection, high VPI was three times more likely to be presented in an interval detected breast cancer compared with a screening detected (OR: 3.0, p<0.0005). Both in univariate and multivariate analysis, high VPI was significantly associated with poor survival (p=0.034 and p=0.022, respectively). In conclusion, activated angiogenesis, estimated by microvessel proliferation, is associated with several markers of aggressive breast cancer phenotype, basal-like 33

34 breast cancer, interval detection, and a significant predictor of prognosis in this series of breast cancer. 1. Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express a new class of intermediate filament protein. Cell Feb 23;60(4): Mokry J, Cizkova D, Filip S, Ehrmann J, Osterreicher J, Kolar Z, et al. Nestin expression by newly formed human blood vessels. Stem Cells Dev Dec;13(6): Mokry J, Ehrmann J, Karbanova J, Cizkova D, Soukup T, Suchanek J, et al. Expression of intermediate filament nestin in blood vessels of neural and non-neural tissues. Acta Medica (Hradec Kralove). 2008;51(3):

35 Abstract poster 6 Prognostic and predictive biomarkers from the stroma of head and neck cancer Daniela Elena Costea, Allison Hills, Gabriella Kalna, Johanna Thurlow, Anne Christine Johannessen and Max Partridge. Departemnt of Pathology, The Gade Institute, Haukeland University Hospital and University of Bergen, Norway, Centre for Stem Cell Biology,Department of Biomedical Science, University of Sheffield, UK, Beatson Institute for Cancer Research, Glasgow, UK, and Guy s and St. Thomas Hospitals, London, UK Introduction Changes in the epithelia result in concomitant adaptations by the fibroblasts as a carcinoma evolves but what these are and how they modulate invasion is poorly understood. Carcinoma associated fibroblasts (CAF) are known to be heterogeneous but distinct subtypes have not been identified. Methods CAFs and normal fibroblasts (NF) were isolated from head and neck squamous cell carcinomas (HNSCC) and normal oral mucosa and maintained in 3D culture to mimic the in vivo microenvironment. Gene expression profiling was performed using Affymetrix arrays and QRTPCR. Migratory characteristics were evaluated using transwell and adhesion assays and video microscopy. Levels of growth factors and cytokines were determined by ELISA. Results Significantly changed gene pathways in CAFs included regulation of substrate adhesion, tissue remodeling, cell migration, secretion, growth regulation and angiogenesis. One third of the over expressed genes were TGFB1 targets and predicted for reduced disease-free survival. CAFs fell broadly into 2 groups. The first group supported deep invasion of malignant keratinocytes, had a gene expression profile closer to NF, were more adhesive than NF, showed rapid migration in response to TGFB1 and secreted high levels of hyaluronic acid, KGF and HGF. The second group supported only limited invasion, were genetically divergent to NF and relatively stationary cells that secreted high levels of TGFB1 but did not respond to this growth factor. Conclusions 35

36 This study identified few key stromal prognostic and predictive markers for HNSCC and unraveled the heterogeneity of CAF cell population. 36

37 PÅSKEEGG 1 Nguyen Tan Dat LIS ved Nordlandssykehuset i Bodø Sykehistorie: 30 år gammel mann: Utflod i urinrøret siste 2 uker, smerte og svie ved vannlating. Afebril, ingen nattesvette. Klinisk undersøkelse: Venstre testikkel med en tumor som måler ca 2,5 x 1,5 cm, mot venstre testikkels pol, glatt overflate, uøm. UL av testis: I venstre testis foreligger en ca 2,3 cm stor hypoekkoisk velsirkulert oppfylning som er cancer suspekt. På samme side og ekstratestikulært sees en ca 1,3 cm stor oppfylning med samme ekkogenisitet; metastasesuspekt i epididymis. Upåfallende høyre testis. Konklusjon: Oppfylning i venstre testis som er sterkt malignitetsuspekt. Makro: 7 x 5 x 4 cm testis med 10 cm lang funikkel. Snittflaten viser hemorrhagisk, mørkebrun, velavgrenset tumor på ca 2,7 cm i diameter rundt testis (øvre pol, paratestikulært), som presser på/invaginerer både testis og epididymis. En annen knute ca 1cm i diameter nær epididymis med liknende morfologi. Resterende testis er upåfallende. Mikro: Testis og epididymis med en tumor som presser på begge to. Tumoren er velavgrenset med en fibrøs kapsel som ligger mellom tumoren og normalt vev (testis og epididymis). Tumor invaginerer og vokser inne i testis. Tumorvev består av normalt miltvev (med rød og hvit pulpa). Tumoren viser ingen positiv reaksjon for keratin, PLAP, AFP eller calretinin. CD31 og CD34 er positive i endotel. Testikulært vev ser normalt ut med normal spermatogenese, atypi eller in situ karsinom ikke påvist (bekreftet med negativ PLAP farging). Funikkel og tunica er normale. Bildet forenlig med miltvev i testis og med såkalt splenic gonadal fusion. Diagnose: Testis med miltvev 'Splenic-gonadal fusion'. Diskusjon: Splenic gonadal fusion: En sjelden tilstand hvor færre enn 100 tilfeller har vært rapportert, og som vanligvis involverer venstre testikkel. Splenic-gonadal fusion forekommer i to former: kontinuerlig og usammenhengende. Den kontinuerlige varianten viser en forbindelse mellom abdominal milt og skrotalt ektopisk miltvev; forbindelsen kan være rent miltvev, bindevev, eller begge deler. I den usammenhengende formen, som i vårt tilfelle, er det ingen sammenheng mellom abdominal milt og det skrotale ektopiske miltvevet. Splenic gonadal fusion antas å være en utviklingsmessig anomali som oppstår mellom 5 og 8 uker i fosterlivet når milten og gonadale anlegg er topografisk fusjonert sammen. Det er 37

38 signifikant at splenic gonadal fusion ofte er forbundet med høy forekomst av medfødte anomalier som micrognathia og peromelia (alvorlig feil i ekstremitetene). I de rapporterte tilfellene varierte alder på pasientene fra spedbarn til 69 år, og de fleste pasientene var barn eller tenåringer. Tilstanden er dominerende hos kaukasiske individer. Selv om det kan presentere seg med en skrotal eller inguinal masse, eller skrotal ømhet, er det vanligvis et tilfeldig funn. Omtrent 25 % av tilfellene rapportert hittil har vært forbundet med kryptorchide testikler. Splenic gonadal fusion er vanligvis en diskret, liten masse (men kan være så stor som 12 cm), som nesten alltid er fusjonert til øvre pol av testikkel eller til caput epididymis. Makroskopisk og mikroskopisk utseende ligner normalt miltvev, separert fra testikulært vev av en fibrøs kapsel. Områder med fibrose, forkalkning, hemosiderin avleiring, og trabekulær fortykning har vært rapportert. Kasuset skiller seg fra modent teratom fordi det mangler andre modne vevstyper som for eksempel: brusk, bein, thyroideakjertler, hudadnex osv. Kilder: Diagnostic histopathology of tumors. Edited by Christopher D.M. Fletcher. Volume 1. Second edition. Churchill Livingstone. Pp. 812, H NLSH. 38

39 PÅSKEEGG 2 Christina Vogt, Avdeling for patologi og medisinsk genetikk, St. Olavs hospital, Trondheim Sykehistorie 27 år gammel kvinne, P2G1. Rutine prenatal ultralydundersøkelse viste bilateral hydronefrose og hydroureter. Det ble også registrert hydrops, pericard- og pleuravæske, og mor ble digitalisert på grunn av føtal tachyarytmi. Barnet ble forløst med sectio i svangerskapsuke 35. Fødselsvekt 2900 g, lengde 48 cm. Postnatalt ble det også påvist analatresi. Echocardiografi viste dilatert høyre hjerte, og det ble kun påvist to lungevener. Barnet utviklet pulmonal hypertensjon og uventet respirasjonssvikt som ikke responderte på intensiv behandling og døde 18 timer etter fødselen. Makroskopisk undersøkelse Ved obduksjon av barnet ble det funnet luftfattige lunger, for øvrig var de upåfallende og ikke hypoplastiske. Det var normalt innløp av lungevener i venstre atrium. Prenatalt påvist bilateral hydroureter og hydronefrose ble bekreftet, og det ble funnet en bakre uretraklaff med dilatert urinblære. Det forelå også analatresi, agenesi av appendiks og en tumor i thyroidea som ble oppfattet som et hamartom. Hjertet var normalt ved obduksjon. Sinusknuten og A-V knuten ble dissektert ut og seriesnittet uten at det ble funnet patologi. Mikroskopisk undersøkelse av lungene Det forelå betydelig stuvning i kar beliggende i brede alveolsepta. Alveolene var små og runde kledt av et kubisk epitel og de var uten kontakt med kapillærer. Media i små arterier i nærheten av luftveiene var fortykket som ved pulmonal hypertensjon. Omkring disse arteriene ble det funnet ektatiske vener lokalisert nærmest i en ring omkring arterien, og noen steder kunne man se at de hadde felles adventitia. Diagnose : Alveolær kapillær dysplasia med feilplassering av lungevener Diskusjon Alveolær kapillær dysplasia med feilplassering misalignment av lungevener er en sjelden, letal utviklingsanomali som affiserer både lungeparenchym og karforsyning. Opptreden av familiære tilfeller antyder en genetisk årsak. Barna er som regel normale ved fødsel, men utvikler raskt respirasjonsproblemer, hypoksemi og pulmonal hypertensjon, vanligvis i neonatalperioden. De responderer ikke på assistert ventilasjon og økt oksygen konsentrasjon, og dør vanligvis i løpet av noen dager. Typiske funn er feilplassering av små lungevener nær bronkioler og små arterier, nedsatt kapillærtetthet i septa og underutvikling av lobuli. Normalt skjer drenasje av venøst kapillært blod til vener i septa og ikke til den bronkovasculære bunten. Den manglende innvekst av alveolære kapillærer resulterer i manglende luft-blod barriere. Hos omtrent en tredjedel foreligger det også lymfangiektasier. Ved denne tilstanden foreligger det andre organanomalier, spesielt urogenitale, gastrointestinale og kardiovaskulære i ca. 75 % av tilfellene, i vårt tilfelle hadde barnet flere andre utviklingsanomalier. 39