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Diferenciální diagnostika vřetenobuněčných lézí trávicího traktu

Upozornění: Informace získané z popisných dat či souborů uložených v Repozitáři závěrečných prací nemohou být použity k výdělečným účelům nebo vydávány za studijní, vědeckou nebo jinou tvůrčí činnost jiné osoby než autora.
Název:
Diferenciální diagnostika vřetenobuněčných lézí trávicího traktu
Název v angličtině:
Diagnostic morphological features of PDGFRA-mutated gastrointestinal
Typ:
Disertační práce
Autor:
doc. MUDr. Ondřej Daum, Ph.D.
Školitel:
prof. MUDr. Ondřej Hes, Ph.D.
Oponenti:
prof. MUDr. Václav Mandys, CSc.
prof. MUDr. Jiří Ehrmann, CSc.
doc. MUDr. Josef Zámečník, Ph.D.
Id práce:
113145
Fakulta:
Lékařská fakulta v Plzni (LFP)
Pracoviště:
Šiklův ústav patologie (14-500)
Program studia:
Patologie (P5145)
Obor studia:
-
Přidělovaný titul:
Ph.D.
Datum obhajoby:
12. 4. 2007
Výsledek obhajoby:
Prospěl/a
Jazyk práce:
Čeština
Abstrakt:
MUDr. Ondřej Daum DIFERENCIÁLNÍ DIAGNOSTIKA VŘETENOBUNĚČNÝCH LÉZÍ TRÁVICÍHO TRAKTU DIFFERENTIAL DIAGNOSTICS OF SPINDLE CELL LESIONS OF THE DIGESTIVE TRACT UNIVERZITA KARLOVA V PRAZE LÉKAŘSKÁ FAKULTA V PLZNI Šiklův ústav patologie FN a LF UK Plzeň, 2006 Dizertační práce byla zpracována v rámci kombinované formy postgraduálního studia na Šiklově ústavu patologie FN a LF UK v Plzni v letech 2004-2006. Doktorand: MUDr. Ondřej Daum Školitel: Doc. MUDr. Ondřej Hes, PhD. docent Lékařské fakulty UK, Šiklův ústav patologie FN a LF UK v Plzni Oponenti: Prof. MUDr. Václav Mandys, CSc. přednosta Ústavu patologie FN Královské Vinohrady a 3. LF UK v Praze Doc. MUDr. Jiří Ehrmann, PhD. docent Lékařské fakulty UP, Ústav patologie FN a LF UP v Olomouci Doc. MUDr. Josef K. Zámečník, PhD. docent Lékařské fakulty UK, Ústav patologie FN Motol a 2. LF UK v Praze Stanoviska k dizertaci vypracovala Lékařská fakulta UK v Plzni. Autoreferát byl odeslán dne .. Obhajoba se koná dne .. 2007 v .. hod. před komisí pro obhajoby doktorských dizertací v oboru patologická anatomie v.. S dizertační prací je možné se seznámit na děkanátu LF UK v Plzni v Husově ulici, č.p. 13. Prof. MUDr. Michal Michal předseda oborové rady 1 Obsah: 1. Úvod..4 1.1. Úvod..4 1.2. Introduction..5 2. Cíle dizertační práce..8 3. Materiál a metodika..9 4. Výsledky s uvedením nových poznatků a závěrů pro realizaci a další rozvoj vědní disciplíny..10 4.1. Diagnostic morphological features of PDGFRA-mutated gastrointestinal stromal tumors: Molecular genetic and histological analysis of 60 cases of gastric GISTs..10 4.1.1. Souhrn..10 4.1.2. Summary..11 4.2. Gastrointestinal stromal tumor of the pancreas: case report with documentation of KIT gene mutation..11 4.2.1. Souhrn..11 4.2.2. Summary..12 4.3. Gastrointestinální stromální tumor: současný pohled..13 4.3.1. Souhrn..13 4.3.2. Summary..14 4.4. Vanek´s tumor (inflammatory fibroid polyp). Report of 18 cases and comparison with three cases of original Vanek´s series..15 4.4.1. Souhrn..15 4.4.2. Summary..16 4.5. Reactive nodular fibrous pseudotumors of the gastrointestinal tract: report of 8 cases..17 2 4.5.1. Souhrn..17 4.5.2. Summary..18 5. Ohlas autorových publikací k danému tématu..19 5.1. Citace..19 5.2. Ocenění..21 6. Seznam všech autorových publikací..22 7. Přehled použité literatury..23 3 1. Úvod 1.1. Úvod Vřetenobuněčné léze trávicího traktu představují závažný diferenciálně diagnostický problém, protože představují širokou skupinu reaktivních nenádorových, benigních nádorových i maligních nádorových afekcí s mnohdy téměř identickým histologickým obrazem, avšak odlišnou histogenezou, prognózou a hlavně terapeutickými implikacemi. Tato dizertační práce je souborem autorových publikací pojednávajících o těchto lézích. Jde o pět publikací v odborných časopisech, z toho čtyři v zahraničních časopisech, ve dvou případech s impact factorem. Nejdůležitější a zároveň nejčastější jednotkou této skupiny je gastrointestinální stromální tumor (GIST). Nutnost jeho odlišení od benigních lézí spočívá ve faktu, že prakticky všechny tyto nádory musí být považovány za potenciálně maligní. Na druhou stranu, odlišení od leiomyosarkomu, maligního nádoru histologicky velmi napodobujícího GIST, je důležité z důvodu možnosti terapeutického ovlivnění GISTu moderními specifickými inhibitory receptorových tyrosinkináz, jejichž dysregulace je pokládána za klíčovou v onkogenezi tohoto nádoru (imatinib mesylát, sunitinib maleát). Autorovy publikace podávají jednak souhrn současných znalostí o GISTu, dále nově uvádějí extragastrointestinální stromální tumor hlavy pankreatu do klinické diferenciální diagnózy nádorů tohoto orgánu, a konečně představují potenciální histologické a imunohistochemické markery různých typů onkogenních mutací v GISTu, jejichž používání může časově i finančně zefektivnit molekulárně genetické vyšetření tohoto tumoru. Druhou studovanou lézí je Vaňkův tumor (inflammatorní fibroidní polyp), dosud považovaný za nenádorovou reaktivní proliferaci, jejíž diferenciální diagnostika je shrnuta v komentované práci. Práce se také zabývá existencí dvou morfologických typů Vaňkova tumoru, které mohou být, v souladu s histologickými, ultrastrukturálními a 4 imunohistochemickými znaky proliferujících buněk, interpretovány jako dvě zcela odlišné léze tradičně souhrnně označované jako inflammatorní fibroidní polyp, nebo jako různé vývojové fáze jediné entity. Třetí vřetenobuněčnou afekcí studovanou autorem je reaktivní nodulární fibrózní pseudotumor (RNFP), přičemž komentovaná práce, ve světové literatuře druhá v pořadí pojednávající o RNFP, rozšířila známé spektrum vzhledu této léze, a to zejména o variace intercelulárního stromatu, které mohou napodobovat jiné intraabdominální vřetenobuněčné proliferace, zejména nodulární fasciitidu či kalcifikující fibrózní pseudotumor. Dále byla významným novým nálezem exprese cytokeratinů o nízké molekulární hmotnosti, která by mohla svědčit pro původ této léze z multipotentních subserózních buněk. Klíčová slova: vřetenobuněčné léze, GIST, stromální tumor, Vaňkův tumor, inflammatorní fibroidní polyp, reaktivní nodulární fibrózní pseudotumor, RNFP, histologie, ultrastruktura, imunohistochemie, molekulární genetika. 1.2. Introduction Spindle cell lesions represent an important differential diagnostic problem due to the wide spectrum of reactive non-neoplastic, benign neoplastic, and malignant neoplastic affections that may present with virtally identical spindle cell histological pattern despite significant differences in histogenesis, prognosis, and therapeutic implications. The dissertation paper is a set of author´s journal articles with respect to the differential diagnostics of spindle cell lesions of the digestive tract. The set includes five journal articles, four of them published abroad, two of them in journal with impact factor. 5 The most important and most frequent entity of this category is gastrointestinal stromal tumor (GIST). The potential malignancy of all cases of this neoplasm makes its differentiation from benign lesions necessary. On the other hand, differentiating between GIST and its frequent mimic, leiomyosarcoma, is important because of the possibility of treatment of GIST by novel specific inhibitors of receptor tyrosine-kinases that are targets of oncogenic dysregulation (imatinib mesylate, sunitinib malate). Author´s journal articles summarize current concepts of probable oncogenesis, differential diagnostics, and prognostic and therapeutic prediction. Besides that, the articles suggest extragastrointestinal stromal tumor of the pancreas as a novel entity in the clinical differential diagnosis of pancreatic tumors, and offer some histological and immunohistochemical markers of different oncogenic mutations in GISTs that may make their molecular genetic investigation less time and money consuming. The second studied lesion is Vanek´s tumor (inflammatory fibroid polyp) which is regarded as a reactive non-neoplastic proliferation of spindle cells. The paper not only summarizes the differential diagnosis of this peculiar lesion, but also highlights the fact of existence of two histological variants of Vanek´s tumor that may, regarding histological, ultrastructural and immunohistochemical features of proliferating cells, be interpreted either as two different lesions traditionally being designated as inflammatory fibroid polyp, or as different evolutional stages of the only one entity. The third spindle cell lesion which is the subject of the paper is reactive nodular fibrous pseudotumor (RNFP). The author´s journal article, being the second report on this topic in the world literature, widened the known histological spectrum of RNFP, mainly regarding the variations of intercellular stroma, which may closely mimic other intra- abdominal spindle cell prolifrations, namely nodular fasciitis or calcifying fibrous pseudotumor. Furthermore, the newly recognized immunoexpression of low molecular weight 6 cytokeratins in the cells of RNFP suggests the possibility that this lesion is related to a proliferation of multipotential subserosal cells. Key words: spindle cell, GIST, stromal tumor, Vanek´s tumor, inflammatory fibroid polyp, reactive nodular fibrous pseudotumor, RNFP, histology, ultrastructure, immunohistochemistry, molecular genetics. 7 2. Cíle dizertační práce Cílem publikovaných prací bylo nalezení diferenciálně diagnostických histologických, imunohistochemických, ultrastrukturálních a molekulárně genetických znaků, které by dovolily správně klasifikovat vybrané jednotky spadající do spektra vřetenobuněčných lézí trávicího traktu. Dále bylo upozorněno na variabilitu těchto jednotek a případně i předloženy hypotézy, které tuto variabilitu vysvětlují. V problematice gastrointestinálního stromálního tumoru byly hledány i znaky umožňující odlišení variant způsobených různými onkogenními mutacemi, což může mít důsledky i pro stanovení adekvátní terapie. 8 3. Materiál a metodika Hlavním zdrojem materiálu pro studium vřetenobuněčných lézí trávicího traktu byl archiv bioptického materiálu Šiklova ústavu patologie FN a LF UK v Plzni a konzultační Registr nádorů přednosty Šiklova ústavu patologie Prof. Michala Michala. Použit byl nejen vlastní archivní materiál, ale i případy zaslané z jiných patologických ústavů v České republice a ze zahraničí (Japonsko, SRN, Slovenská republika). Materiál byl fixován ve 4% formaldehydu a zpracován standardní metodikou. Řezy z parafinových bločků byly obarveny základními histologickými barvivy a některými vybranými histochemickými a imunohistochemickými metodami, jak je blíže uvedeno v souhrnech jednotlivých publikací. Vizualizace primárních protilátek byla provedena za použití supersensitivního streptavidin-biotin-peroxidázového detekčního systému (Biogenex, San Ramon, CA). Materiál pro elektronovou mikroskopii byl fixován v glutaraldehydu a rutinně zpracován. Izolace DNA pro molekulárně genetická vyšetření byla provedena z 10 μm řezů formalínem fixované, v parafínu zalité tkáně pomocí DNeasy Tissue Kit (QIAgen, Hilden, Germany). Po amplifikaci fragmentů DNA pomocí PCR byla provedena analýza mutací heteroduplexní analýzou při gelové elektroforéze s teplotním gradientem (TGGE) (Biometra, Goettingen, Germany) a sekvenací na automatickém sekvenátoru ABI Prism 3100 Avant (PE/Applied Biosystems), jak je uvedeno v metodické části jednotlivých publikací. 9 4. Výsledky s uvedením nových poznatků a závěrů pro realizaci a další rozvoj vědní disciplíny 4.1. Daum O., Grossmann P., Vanecek T., Sima R., Mukensnabl P., Michal M. (2006): Diagnostic morphological features of PDGFRA-mutated gastrointestinal stromal tumors: Molecular genetic and histological analysis of 60 cases of gastric GISTs. Ann. Diagn. Pathol. In Press 4.1.1. Souhrn Byla provedena analýza vztahu morfologických znaků a přítomnosti mutací genů KIT a PDGFRA u 60 gastrointestinálních stromálních tumorů (GIST) žaludku. Soubor zahrnoval nádory pocházející od 27 mužů a 33 žen, průměrný věk byl 63,8 let (rozmezí 12 až 92 let). Pouze jeden z tumorů pocházel od dívky mladší 21 let. Mutace KIT genu byly detekovány v 31 případech (51,7%), mutace PDGFRA genu v 22 případech (36,7%), zatímco 7 tumorů (11,7%) mělo divoké alely KIT a PDGFRA genů. Korelace výsledků mutační analýzy s histologickými znaky tumorů prokázala, že přítomnost epiteloidních nádorových buněk a infiltrace nádoru žírnými buňkami jsou nejvýznamější znaky mutace PDGFRA genu. Nádorové rhabdoidní buňky a nádorové vícejaderné buňky, které také někteří autoři uvádějí jako typické pro GIST s mutací PDGFRA genu, se v našem souboru jevily jako méně specifické markery, a tumor infiltrující lymphocyty a myxoidní stroma jako atributy zcela beze vztahu k mutačnímu profilu GISTu. Zhodnocení histomorfologie GISTu tak umožňuje volbu cílenějšího molekulárně genetického vyšetření a tedy i časnější diagnózu a účelnější využití finančních prostředků. 10 4.1.2. Summary In this study, 60 gastrointestinal stromal tumors (GISTs) of the stomach were analyzed to elucidate the possible relation of their morphology to mutation status of KIT and PDGFRA genes. The patients included 27 men and 33 women with a mean age of 63.8 years (range 12 to 92). Only one tumor occurred before the age of 21 years. KIT mutations were detected in 31 cases (51,7%), PDGFRA mutations in 22 cases (36,7%), and seven cases (11,7%) were KIT and PDGFRA wild type. When the mutation status was correlated with histological features of the tumors, epithelioid or mixed epithelioid/spindle cell pattern and mast cell infiltration were found as the most reliable signs of PDGFRA mutation. Neoplastic rhabdoid cells and multinucleated giant cells, also previously reported as features of PDGFRA mutated GISTs, seemed to be less specific but still helpful markers in our study. Finally, tumor infiltrating lymphocytes and myxoid stroma do not seem to be valuable histological signs. 4.2. Daum O., Klecka J., Ferda J., Treska V., Vanecek T., Sima R., Mukensnabl P., Michal M. (2005): Gastrointestinal stromal tumor of the pancreas: case report with documentation of KIT gene mutation. Virchows Arch. 446, 470-472 4.2.1 Souhrn Gastrointestinální stromální tumor (GIST) je nejčastější mesenchymální nádor trávicí trubice. Přestože bývá vzácněji popisován i v některých extragastrointestinálních lokalizacích, jako ve žlučníku, močovém měchýři, omentu a mesenteriu, až do konce roku 2003 nebyl popsán molekulárně geneticky prokázaný GIST pankreatu. Tato kazuistika popisuje případ (extra)gastrointestinálního stromálního tumoru, tedy (E)GISTu hlavy pankreatu u 70-leté 11 ženy. Nádor byl dobře ohraničený, pružný, bílý, s centrální dutinou. Největší rozměr tumoru byl 5 cm. Histologicky byl tvořen především vřetenitými buňkami s relativně četnými perinukleárními vakuolami. Skeinoidní vlákna byla dobře patrná. V centrální části nádoru byla přítomna perivaskulární hyalinizace, myxoidní změny, ložiska nekrózy a cystické degenerace. Mitotický index byl 2 mitózy/50 zorných polí velkého zvětšení (HPF). Nádorové buňky vykazovaly imunoexpresi vimentinu, KIT proteinu a hladkosvalového aktinu. Molekulárně genetické vyšetření tumoru prokázalo deleci 6 bazí v exonu 11 genu c-kit. Podle našeho přesvědčení založeného na vyhledávání literatury v elektronických databázích je toto první případ adekvátně (imunohistochemicky a molekulárně geneticky) diagnostikovaného GISTu klinicky se prezentujícího jako tumor pankreatu. 4.2.2. Summary Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gut. Although it was occasionally described in some extragastrointestinal sites, such as gallblader, urinary bladder, omentum and mesentery, there are no reports on its occurence in the pancreas until the end of 2003. This report describes a gastrointestinal stromal tumor of the pancreatic head in a 70-year-old woman treated by Whipple´s hemipancreatoduodenectomy. The tumor was well demarcated, rubbery, white, with central cystic changes. Its greatest diameter was 5 cm. Histologically, it was composed predominantly of spindle cells with occasional perinuclear vacuoles. Skeinoid fibers were readily discernible. Perivascular hyalinization, myxoid changes, necrotic foci and cystic degeneration occured in central parts of the tumor. Mitotic index was 2 mitoses/50 HPF. The lesion showed immunocytochemical reactivity for vimentin, KIT protein, smooth muscle actin and muscle specific actin. Molecular genetic evaluation revealed deletion of 6 base pairs in exon 11 of c-kit. Finally, the tumor was 12 diagnosed as GIST of the head of the pancreas. To the best of our knowledge, there have been no other properly documented cases of pancreatic GIST reported in the world literature. 4.3. Daum O., Vaněček T., Šíma R., Michal M. (2006): Gastrointestinální stromální tumor: současný pohled. Klinická onkologie 19, 203-211 4.3.1. Souhrn Gastrointestinální stromální tumor je nejčastější mesenchymální nádor trávicího traktu. V současné době je definovaný jako nádor tvořený vřetenitými a/nebo epiteloidními buňkami, jejichž fenotyp odpovídá diferenciaci v Cajalovy interstitiální buňky. Většinou jsou tyto nádorové buňky pozitivní v imunohistochemickém průkazu KIT proteinu a u téměř všech těchto tumorů lze prokázat mutaci genu c-kit nebo PDGFRA kódující transmembránové proteiny zařazené do III. třídy receptorových tyrosinkináz. Nejčastěji se gastrointestinální stromální tumor vyskytuje v žaludku, méně často v ostatních částech trávicí trubice, vzácně i v extragastrointestinální lokalizaci, a to v mesenteriu, omentu, retroperitoneu, žlučníku, močovém měchýři, pankreatu a ve vagině. Ve většině případů je možná poměrně spolehlivá diagnóza z konvenčního barvení hematoxylinem a eosinem ve světelné mikroskopii. Pomocnými diagnostickými metodami je imunohistochemický průkaz KIT proteinu (CD117) a průkaz mutace genu c-kit nebo PDGFRA. Negativita těchto vyšetření však diagnózu nevylučuje. Každý gastrointestinální stromální tumor je třeba považovat za potenciálně maligní. Riziko agresivního chování se v současné době stanovuje na základě mitotického indexu a maximálního rozměru nádoru. Mutační analýza umožňuje predikovat odpověď tumoru na terapii imatinib mesylátem. 13 4.3.2. Summary Gastrointestinal stromal tumor is the most frequent mesenchymal tumor of the alimentary tract, currently being defined as a tumor composed of spindle and/or epithelioid cells presumably differentiating towards interstitial cells of Cajal. The majority of these tumors are KIT – immunoreactive and almost all carry mutated c-kit or PDGFRA gene encoding two transmembrane class III tyrosinkinases. The most frequent location of gastrointestinal stromal tumor is stomach followed by other sites of gastrointestinal tract. Occasional sites of occurrence are mesenterium, omentum, retroperitoneum, gallbladder, urinary bladder, pancreas and vagina. Light microscopic examination of slides stained with haematoxylin and eosin is highly reliable in most cases. Useful ancillary diagnostic techniques are immunohistochemical investigation with antibodies against KIT protein (CD117) and detection of mutations of either c-kit or PDGFRA genes. Nevertheless, negative results do not exclude histologically proven diagnosis. All gastrointestinal stromal tumors should be regarded as potentially malignant with risk of aggressive behavior being determined on the basis of mitotic count and the largest diameter of the tumor. Mutational status of the neoplasm serves as a predictor of therapeutic response to imatinib mesylate. 14 4.4. Daum O., Hes O., Vanecek T., Benes Z., Sima R., Zamecnik M., Mukensnabl P., Hadravska S., Curik R., Michal M.(2003): Vanek´s tumor (inflammatory fibroid polyp). Report of 18 cases and comparison with three cases of original Vanek´s series. Ann. Diagn. Pathol. 7, 337-347 4.4.1. Souhrn Soubor představuje osmnáct případů Vaňkova tumoru. Mezi pacienty bylo devět mužů a devět žen, jejichž věk se pohyboval v rozmezí 45 až 93 let (průměrný věk 66,2 let). Devět případů bylo klinicky diagnostikováno jako polyp žaludečního antra, pět jako polyp žaludku (blíže neurčeno), jeden polyp byl lokalizován v ileu a tři zbývající v tenkém střevě (blíže neurčeno). Velikost byla známa u třinácti polypů. U těchto se největší rozměr pohyboval od 0,4 do 5 cm (průměr 2,2 cm). Imunohistochemicky byly afekce pozitivní v průkazu vimentinu (18/18) a antigenu CD34 (15/18). Všechny případy negativní v průkazu CD34 také postrádaly koncentrické formace vřetenitých buněk okolo žlázek a cév. Rozdílný imunofenotyp a absence koncentrických formací může být vysvětlena existencí dvou různých lézí běžně společně označovaných jako Vaňkův tumor (inflamatorní fibroidní polyp), nebo hypotézou o různých vývojových stadiích jedné entity. V diferenciální diagnóze je třeba odlišit zejména eosinofilní gastroenteritidu, gastrointestinální stromální tumor, inflamatorní pseudotumor, hemangioendoteliom a hemangiopericytom. Narozdíl od gastrointestinálního stromálního tumoru, molekulárně genetické vyšetření neprokázalo substituci, deleci ani inserci v exonech 11 a 9 genu c-kit v žádném z analyzovaných Vaňkových tumorů. 15 4.4.2. Summary Eighteen cases of Vanek’s tumors are presented. The patients included nine men and nine women between the ages of 45 and 93 years (mean age 66.2 years). Nine cases were clinically diagnosed as polyps of the gastric antrum, five cases as polyps of the stomach (not otherwise specified), one polyp was located in the ileum and the three remaining ones in the small intestine (not otherwise specified). The thirteen polyps with the available information of their size measured from 0.4 to 5 cm in the greatest diameter (mean 2.2 cm). Immunohistochemically, the affections were positive for vimentin (18/18) and CD34 (15/18). All the cases negative for CD34 also lacked concentric onion-skin-like formations of the spindle cells around glands and vessels. The different immunophenotype and the absence of concentric formations could be explained by the existence of two different lesions commonly designated as Vanek’s tumor (inflammatory fibroid polyp) or by the hypothesis of various evolutional stages. In the differential diagnosis it is important to distinguish namely eosinophilic gastroenteritis, gastrointestinal stromal tumor, inflammatory pseudotumor, hemangioendothelioma and hemangiopericytoma. In contrast to gastrointestinal stromal tumors, genetically no substitution, deletion or insertion occurred in c-kit exon 11 in all analyzed samples. Likewise, no deletion or insertion in part of c-kit exon 9 was observed. 16 4.5. Daum O., Vanecek T., Sima R., Curik R., Zamecnik M., Yamanaka S., Mukensnabl P., Benes Z., Michal M. (2004): Reactive nodular fibrous pseudotumors of the gastrointestinal tract: report of 8 cases. Int. J. Surg. Pathol. 12, 365-374 4.5.1 Souhrn Studie prezentuje osm případů reaktivního nodulárního fibrózního pseudotumoru gastrointestinálního traktu. Soubor pacientů byl tvořen šesti muži a dvěma ženami, věkové rozmezí bylo 1 - 68 let (průměrný věk 41,5 roku). Pět lézí bylo lokalizováno v tlustém střevě. Z těchto byly dvě v sigmatu, jedna v céku, jedna v appendixu a u jedné nebyla lokalizace v tlustém střevě blíže specifikována. Zbývající tři případy postihovaly tenké střevo. Největší rozměr těchto tumoriformních útvarů se pohyboval v rozmezí 3 až 10 cm (průměr 6,2 cm). Histologicky byly afekce tvořeny hvězdicovitými nebo vřetenitými buňkami připomínajícími fibroblasty v nepravidelném uspořádání nebo tvořícími krátké svazky, uloženými ve stromatu bohatým na kolagen, s řídce disperzními mononukleárními zánětlivými elementy často tvořícími lymfoidní folikly. Imunohistochemicky byly vřetenité a hvězdicovité buňky pozitivní v průkazu vimentinu (7/7), hladkosvalového aktinu (8/8), aktinu specifického pro svalovinu (5/7), cytokeratinů protilátkou AE1/AE3 (6/7) a CAM 5.2 (1/7), a antigenu CD68 (1/7). Žádný případ (0/8) nereagoval s protilátkou proti antigenu CD117 (c-kit). Narozdíl od gastrointestinálního stromálního tumoru také molekulárně genetické vyšetření neprokázalo substituci, deleci ani inserci v exonech 11 a 9 genu c-kit v žádném z analyzovaných reaktivních nodulárních fibrózních pseudotumorů. Elektronmikroskopické vyšetření vřetenitých buněk prokázalo ultrastrukturální znaky myofibroblastů. Vzhledem k výše uvedeným výsledkům histologického, imunohistochemického a elektronmikroskopického vyšetření, zvláště vzhledem k imunoexpresi cytokeratinů o nízké molekulární hmotnosti, 17 předpokládáme, že jde o proliferaci of multipotentních subserózních buněk spíše než běžných myofibroblastů či fibroblastů. 4.5.2. Summary Eight cases of reactive nodular fibrous pseudotumor of the gastrointestinal tract are presented. The patients included six men and two women between the ages of 1 and 68 years (mean age 41.5 years). Five of the investigated lesions were located in the large bowel. Of these, two originated in the sigmoid colon, one in the cecum, one in the appendix and one in the large bowel not otherwise specified. The remaining three tumors involved the small intestine. The tumors´ size reached from 3 to 10 cm in the greatest diameter (mean 6.2 cm). Histologically, they were composed of stellate or spindle cells resembling fibroblasts arranged haphazardly or in intersecting fascicles, embedded in a collagen-rich stroma with sparse intralesional mononuclear cells frequently arranged in lymphoid aggregates. Immunohistochemically, the affections were positive for vimentin (7/7), smooth muscle actin (8/8), muscle specific actin (5/7), cytokeratins AE1/AE3 (6/7) and CAM 5.2 (1/7), and antigen CD68 (1/7). No case (0/8) reacted positively with antibodies to CD117 (c-kit). Genetically, no substitution, deletion or insertion occurred in exon 11 in all analyzed samples. Likewise, no deletion or insertions in part of exon 9 were observed. Ultrastructurally, the tumor cells revealed features typical of myofibroblasts. According to the morphologic, immunohistochemical and ultrastructural features mentioned above, especially to the positivity of low-molecular weight cytokeratins, we propose this lesion to be related to a proliferation of multipotential subserosal cells rather than ordinary myofibroblasts or fibroblasts. 18 5. Ohlas autorových publikací k danému tématu 5.1. Citace 5.1.1. Daum O., Klecka J., Ferda J., Treska V., Vanecek T., Sima R., Mukensnabl P., Michal M. (2005): Gastrointestinal stromal tumor of the pancreas: case report with documentation of KIT gene mutation. Virchows Arch. 446, 470-472 Cao D. F., Antonescu C., Wong G., et al. (2006): Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations. Mod. Pathol. 19, 1157-1163 Agaimy A., Wunsch P. H. 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Abstract v angličtině:
Daum O., Grossmann P., Vanecek T., Sima R., Mukensnabl P., Michal M. (2006): Diagnostic morphological features of PDGFRA-mutated gastrointestinal stromal tumors: Molecular genetic and histological analysis of 60 cases of gastric GISTs. Ann. Diagn. Pathol. In Press Summary In this study, 60 gastrointestinal stromal tumors (GISTs) of the stomach were analyzed to elucidate the possible relation of their morphology to mutation status of KIT and PDGFRA genes. The patients included 27 men and 33 women with a mean age of 63,8 years (range 12 to 92). Only one tumor occurred before the age of 21 years. KIT mutations were detected in 31 cases (51,7%), PDGFRA mutations in 22 cases (36,7%), and seven cases (11,7%) were KIT and PDGFRA wild type. When the mutation status was correlated with histological features of the tumors, epithelioid or mixed epithelioid/spindle cell pattern and mast cell infiltration were found as the most reliable signs of PDGFRA mutation. Neoplastic rhabdoid cells and multinucleated giant cells, also previously reported as features of PDGFRA mutated GISTs, seemed to be less specific but still helpful markers in our study. Finally, tumor infiltrating lymphocytes and myxoid stroma do not seem to be valuable histological signs. Daum O., Klecka J., Ferda J., Treska V., Vanecek T., Sima R., Mukensnabl P., Michal M. (2005): Gastrointestinal stromal tumor of the pancreas: case report with documentation of KIT gene mutation. Virchows Arch. 446, 470-472 Summary Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gut. Although it was occasionally described in some extragastrointestinal sites, such as gallblader, urinary bladder, omentum and mesentery, there are no reports on its occurence in the pancreas until the end of 2003. This report describes a gastrointestinal stromal tumor of the pancreatic head in a 70-year-old woman treated by Whipple´s hemipancreatoduodenectomy. The tumor was well demarcated, rubbery, white, with central cystic changes. Its greatest diameter was 5 cm. Histologically, it was composed predominantly of spindle cells with occasional perinuclear vacuoles. Skeinoid fibers were readily discernible. Perivascular hyalinization, myxoid changes, necrotic foci and cystic degeneration occured in central parts of the tumor. Mitotic index was 2 mitoses/50 HPF. The lesion showed immunocytochemical reactivity for vimentin, KIT protein, smooth muscle actin and muscle specific actin. Molecular genetic evaluation revealed deletion of 6 base pairs in exon 11 of c-kit. Finally, the tumor was diagnosed as GIST of the head of the pancreas. To the best of our knowledge, there have been no other properly documented cases of pancreatic GIST reported in the world literature. Daum O., Vaněček T., Šíma R., Michal M. (2006): Gastrointestinální stromální tumor: současný pohled. Klinická onkologie 19, 203-211 Summary Gastrointestinal stromal tumor is the most frequent mesenchymal tumor of the alimentary tract, currently being defined as a tumor composed of spindle and/or epithelioid cells presumably differentiating towards interstitial cells of Cajal. The majority of these tumors are KIT – immunoreactive and almost all carry mutated c-kit or PDGFRA gene encoding two transmembrane class III tyrosinkinases. The most frequent location of gastrointestinal stromal tumor is stomach followed by other sites of gastrointestinal tract. Occasional sites of occurrence are mesenterium, omentum, retroperitoneum, gallbladder, urinary bladder, pancreas and vagina. Light microscopic examination of slides stained with haematoxylin and eosin is highly reliable in most cases. Useful ancillary diagnostic techniques are immunohistochemical investigation with antibodies against KIT protein (CD117) and detection of mutations of either c-kit or PDGFRA genes. Nevertheless, negative results do not exclude histologically proven diagnosis. All gastrointestinal stromal tumors should be regarded as potentially malignant with risk of aggressive behavior being determined on the basis of mitotic count and the largest diameter of the tumor. Mutational status of the neoplasm serves as a predictor of therapeutic response to imatinib mesylate. Daum O., Hes O., Vanecek T., Benes Z., Sima R., Zamecnik M., Mukensnabl P., Hadravska S., Curik R., Michal M.(2003): Vanek´s tumor (inflammatory fibroid polyp). Report of 18 cases and comparison with three cases of original Vanek´s series. Ann. Diagn. Pathol. 7, 337-347 Summary Eighteen cases of Vanek’s tumors are presented. The patients included nine men and nine women between the ages of 45 and 93 years (mean age 66,2 years). Nine cases were clinically diagnosed as polyps of the gastric antrum, five cases as polyps of the stomach (not otherwise specified), one polyp was located in the ileum and the three remaining ones in the small intestine (not otherwise specified). The thirteen polyps with the available information of their size measured from 0,4 to 5 cm in the greatest diameter (mean 2,2 cm). Immunohistochemically, the affections were positive for vimentin (18/18) and CD34 (15/18). All the cases negative for CD34 also lacked concentric onion-skin-like formations of the spindle cells around glands and vessels. The different immunophenotype and the absence of concentric formations could be explained by the existence of two different lesions commonly designated as Vanek’s tumor (inflammatory fibroid polyp) or by the hypothesis of various evolutional stages. In the differential diagnosis it is important to distinguish namely eosinophilic gastroenteritis, gastrointestinal stromal tumor, inflammatory pseudotumor, hemangioendothelioma and hemangiopericytoma. In contrast to gastrointestinal stromal tumors, genetically no substitution, deletion or insertion occurred in c-kit exon 11 in all analyzed samples. Likewise, no deletion or insertion in part of c-kit exon 9 was observed. Daum O., Vanecek T., Sima R., Curik R., Zamecnik M., Yamanaka S., Mukensnabl P., Benes Z., Michal M. (2004): Reactive nodular fibrous pseudotumors of the gastrointestinal tract: report of 8 cases. Int. J. Surg. Pathol. 12, 365-374 Summary Eight cases of reactive nodular fibrous pseudotumor of the gastrointestinal tract are presented. The patients included six men and two women between the ages of 1 and 68 years (mean age 41.5 years). Five of the investigated lesions were located in the large bowel. Of these, two originated in the sigmoid colon, one in the cecum, one in the appendix and one in the large bowel not otherwise specified. The remaining three tumors involved the small intestine. The tumors´ size reached from 3 to 10 cm in the greatest diameter (mean 6,2 cm). Histologically, they were composed of stellate or spindle cells resembling fibroblasts arranged haphazardly or in intersecting fascicles, embedded in a collagen-rich stroma with sparse intralesional mononuclear cells frequently arranged in lymphoid aggregates. Immunohistochemically, the affections were positive for vimentin (7/7), smooth muscle actin (8/8), muscle specific actin (5/7), cytokeratins AE1/AE3 (6/7) and CAM 5.2 (1/7), and antigen CD68 (1/7). No case (0/8) reacted positively with antibodies to CD117 (c-kit). Genetically, no substitution, deletion or insertion occurred in exon 11 in all analyzed samples. Likewise, no deletion or insertions in part of exon 9 were observed. Ultrastructurally, the tumor cells revealed features typical of myofibroblasts. According to the morphologic, immunohistochemical and ultrastructural features mentioned above, especially to the positivity of low-molecular weight cytokeratins, we propose this lesion to be related to a proliferation of multipotential subserosal cells rather than ordinary myofibroblasts or fibroblasts.
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Stáhnout Text práce doc. MUDr. Ondřej Daum, Ph.D. 212 kB
Stáhnout Abstrakt v českém jazyce doc. MUDr. Ondřej Daum, Ph.D. 237 kB
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