Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, Italian Division of the International Academy of Pathology

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1 ISSN Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, Italian Division of the International Academy of Pathology Società Italiana di Anatomia Patologica e Citopatologia diagnostica Divisione Italiana della International Academy of Pathology Vol. 05 October 203 Periodico bimestrale POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n 46 art., comma, DCB PISA Aut. Trib. di Genova n. 75 del 22/06/949 c-iap 6 Congresso Triennale Siapec-Iap Ottobre 203 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology ROMA Hotel Ergife Palace

2 Simposio Roche 6 Congresso Triennale Siapec Hotel Ergife Palace Roma, Ottobre Congresso Triennale Siapec Hotel Ergife Palace Roma, Ottobre Congresso Triennale Siapec Hotel Ergife Palace Roma, Ottobre 203 La Simposio qualità Roche nella determinazione dei La qualità biomarcatori: nella determinazione aspetti clinici e legali dei biomarcatori: aspetti clinici e legali Il percorso Her2 positivo Vincenzo Arena L importanza Il percorso Her2 di Braf positivo nel Vincenzo melanoma Arena Il percorso Her2 positivo Vincenzo Arena metastatico Daniela Massi Dal L importanza rischio clinico di di Braf Braf alla nel nel medicina melanoma legale metastatico Vania Daniela Cirese Massi WORKGROUP Dal rischio clinico alla Caccia medicina all errore: legale Vania cause Cirese e conseguenze Cirese WORKGROUP Caccia all errore: cause e conseguenze 28 Ottobre 203 Ore 3,00-4,00 Sala Orange 2 28 Ottobre 203 3,00-4,00 28 Ottobre 203 3,00-4,00 Sala Orange 2 Sala Orange 2 La Sua opinione sarà il punto di partenza per la discussione La Sua opinione sarà il punto di partenza per la discussione Simposio Roche 6 Congresso Triennale Siapec Hotel Ergife Palace Roma, Ottobre 203 Collegarsi sito La qualità nella determinazione Inserire password biomarcatori203 dei Registrarsi biomarcatori: inserendo i propri dati aspetti clinici e legali Rispondere Il percorso ai 4 Her2 quesiti positivo scientifici Vincenzo Arena Attendere la ricezione dell di conferma L importanza di Braf nel melanoma metastatico Daniela Massi Le risposte saranno spunto di discussione durante il simposio Dal rischio clinico alla medicina legale Vania Cirese 6 Congresso Triennale Siapec WORKGROUP Caccia all errore: cause e conseguenze Hotel Ergife Palace Roma, Ottobre 203

3 Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, Italian Division of the International Academy of Pathology Editor-in-Chief Marco Chilosi, Verona Associate Editor Roberto Fiocca, Genova Managing Editor Roberto Bandelloni, Genova Scientific Board R. Alaggio, Padova G. Angeli, Vercelli M. Barbareschi, Trento C.A. Beltrami, Udine G. Bevilacqua, Pisa M. Bisceglia, S. Giovanni R. A. Bondi, Bologna F. Bonetti, Verona C. Bordi, Parma A.M. Buccoliero, Firenze G.P. Bulfamante, Milano G. Bussolati, Torino A. Cavazza, Reggio Emilia G. Cenacchi, Bologna P. Ceppa, Genova C. Clemente, Milano M. Colecchia, Milano G. Collina, Bologna P. Cossu-Rocca, Sassari P. Dalla Palma, Trento G. De Rosa, Napoli A.P. Dei Tos, Treviso L. Di Bonito, Trieste C. Doglioni, Milano V. Eusebi, Bologna G. Faa, Cagliari F. Facchetti, Brescia G. Fadda, Roma G. Fornaciari, Pisa M.P. Foschini, Bologna F. Fraggetta, Catania E. Fulcheri, Genova P. Gallo, Roma F. Giangaspero, Roma W.F. Grigioni, Bologna G. Inghirami, Torino L. Leoncini, Siena M. Lestani, Arzignano G. Magro, Catania A. Maiorana, Modena E. Maiorano, Bari T. Marafioti, Londra A. Marchetti, Chieti D. Massi, Firenze M. Melato, Trieste F. Menestrina, Verona G. Monga, Novara R. Montironi, Ancona B. Murer, Mestre V. Ninfo, Padova M. Papotti, Torino M. Paulli, Pavia G. Pelosi, Milano G. Pettinato, Napoli S. Pileri, Bologna R. Pisa, Roma M.R. Raspollini, Firenze L. Resta, Bari G. Rindi, Parma M. Risio, Torino A. Rizzo, Palermo J. Rosai, Milano G. Rossi, Modena L. Ruco, Roma M. Rugge, Padova M. Santucci, Firenze A. Scarpa, Verona A. Sidoni, Perugia G. Stanta, Trieste G. Tallini, Bologna G. Thiene, Padova P. Tosi, Siena M. Truini, Genova V. Villanacci, Brescia G. Zamboni, Verona G.F. Zannoni, Roma Editorial Secretariat G. Martignoni, Verona M. Brunelli, Verona Governing Board SIAPEC-IAP President: C. Clemente, Milano Vice President: G. De Rosa, Napoli General Secretary: A. Sapino, Torino Past President: G.L. Taddei, Firenze Members: A. Bondi, Bologna P. Dalla Palma, Trento A. Fassina, Padova R. Fiocca, Genova D. Ientile, Palermo L. Resta, Bari L. Ruco, Roma M. Santucci, Firenze G. Zamboni, Verona Associate Members Representative: T. Zanin, Genova Copyright Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology Publisher Pacini Editore S.p.A. Via Gherardesca, 562 Pisa, Italy Tel Fax Vol. 05 October 203 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

4 Information for Authors including editorial standards for the preparation of manuscripts Pathologica is intended to provide a medium for the communication of results and ideas in the field of morphological research on human diseases in general and on human pathology in particular. The Journal welcomes contributions concerned with experimental morphology, ultrastructural research, immunocytochemical analysis, and molecular biology. Reports of work in other fields relevant to the understanding of human pathology may be submitted as well as papers on the application of new methods and techniques in pathology. The official language of the journal is English. Authors are invited to submit manuscripts according to the following instructions by to: Lisa Andreazzi - Editorial Office Pathologica - c/o Pacini Editore S.p.A. 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5 Società Italiana di Anatomia Patologica e Citopatologia diagnostica Divisione Italiana della International Academy of Pathology 6 Congresso Triennale Siapec-Iap Ottobre 203 ROMA Hotel Ergife Palace

6 4 6 Congresso Triennale Siapec-Iap ROMA Ottobre 203 Comitati Tavole s Sotto l Alto Patronato del Presidente della Repubblica con il Patrocinio dell Ordine Provinciale dei Medici-Chirurghi e degli Odontoiatri di Roma Sabato 26 O Sa Gr St Co CONSIGLIO DIRETTIVO SIAPEC PRESIDENTE Claudio Clemente PAST PRESIDENT Gian Luigi Taddei VICE PRESIDENTE Gaetano De Rosa SEGRETARIO Anna Sapino CONSIGLIERI Arrigo Bondi Paolo Dalla Palma Ambrogio Fassina Roberto Fiocca Domenico Ientile Leonardo Resta Luigi Ruco Marco Santucci Giuseppe Zamboni Rappresentante AITIC Carmelo Lupo PRESIDENTE DEL CONGRESSO Claudio Clemente COMITATO SCIENTIFICO PRESIDENTE Luigi Ruco COMPONENTI Piero Alò Generoso Bevilacqua Claudio Clemente Gaetano De Rosa Angelo Paolo Dei Tos Carlo Della Rocca Vittoria Donofrio Alfredo Fabiano Roberto Fiocca Pietro Gallo Felice Giangaspero Antonio Marchetti Oscar Nappi Andrea Onetti Muda Stefano Pileri Guido Rindi Anna Sapino Gian Luigi Taddei Fabio Maria Vecchio COMITATO ORGANIZZATORE PRESIDENTE Giuseppe Santeusanio COMPONENTI Gerardo Botti Franca Del Nonno Maria Rosaria Giovagnoli Vito Gomez Mirella Marino Ferdinando Quarto Guido Pettinato Antonio Rosario Ricci Patrizia Rigato Raffaele Rossiello Steno Sentinelli Stefania Uccini SEDE Hotel Ergife Palace Via Aurelia, Roma RM Tel Mail: SEGRETERIA ORGANIZZATIVA Sa 9:30 Ce Domenica Sala Sim La p dell uter Sim La d dell endo Lettu Cors La d dei t ovar Slid Gine Via Sassonia, Rimini Tel Mail LEGENDA = Simposi = Gruppi d

7 mitati Tavole sinottiche PROGRAMMA SCIENTIFICO 5 Sabato 26 Ottobre 203 Sala Messalia Sala Orange Sala Orange 2 Sala Terragona Sala Cesarea Sala Mileto Sala Hama Gruppo di Gruppo di Studio Testa Collo Gruppo di Studio GYM studio APCI Gruppo di studio GIPAM Gruppo di Studio Pagine Presentazione FAD ai Gruppi Gruppo di studio NAP Gruppo di Studio GIPAD Gruppo di Studio Qualita Sicurezza e Gestione del rischio in A.P. Gruppo di Studio GIC i IZZATIVA 2 Rimini Sala Plenaria 9:30 Cerimonia Inaugurale e Saluto delle Autorita Domenica 27 Ottobre 203 Sala Plenaria Sala Messalia Sala Orange Sala Orange 2 Sala Tarragona Sala Cesarea Simposio I L Autopsia Oggi Ematopatologia Simposio La patologia della cervice uterina Simposio Neoplasie endocrine/ neuroendocrine di grado intermedio ed alto: stato dell arte Caffè Simposio La diagnostica della biopsia endometriale Simposio II Simposio Ematopatologia Neoplasie endocrine/ neuroendocrine: aspetti molecolari, stato dell arte ed applicazioni pratiche L Autopsia Oggi Lettura magistrale: Infiammazione e Cancro. A. Mantovani, Università di Milano Lunch Corso breve La diagnostica dei tumori ovarici Corso breve Patologia mammaria Patologi Oltre Frontiera Donne che aiutano le donne: patologhe oltre frontiera Caffè Slide Seminar Ginecopatologia LEGENDA = Simposio = Gruppi di Studio Slide Seminar Tumori degli istiociti e delle cellule dendritiche e loro mimi Telepatologia con Patologi Oltre Frontiera Italia-Africa: prove generali di diagnostica digitale = Lettura Magistrale = Corso Breve Simposio Patologia Pediatrica Simposio Patologia Pediatrica Corso breve Diagnostica Definizione di malignità in neoplasie endo- Ultrastrutturale crine e neuroendocrine Slide Seminar Casi difficili ed inusuali = Slide Seminar = Comunicazioni Orali Incontro sui controlli di qualità FISH Comunicazioni orali Patologia Mammaria Comunicazioni orali Patologia Mammaria 2 Comunicazioni orali Uropatologia Comunicazioni orali Patologia dell Osso e dei Tessuti Molli = Sessione Congiunta = Assemblea Societaria

8 6 6 Congresso Triennale Siapec-Iap ROMA Ottobre 203 Tavole sinottiche Lunedì 28 Ottobre 203 Sala Plenaria Sala Messalia Sala Orange Sala Orange 2 Sala Tarragona Sala Cesarea Simposio Patologia digestiva Simposio Simposio Dermatopatologia Update in patologia Novità sulle toraco-polmonare lesioni melanocitiche Caffè Simposio Patologia digestiva Simposio Dermatopatologia Non solo melanoma Tavola rotonda La caratterizzazione molecolare del carcinoma polmonare in funzione della terapia medica: i percorsi diagnostici ottimali Management Simposio in Anatomia Patologica: qualità, sicurezza e gestione del rischio in Anatomia Patologica La diagnostica pre-operatoria nel distretto testa-collo Management Simposio in Anatomia Ruolo del Patologica: patologo nella qualità, sicurezza e gestione del rischio in Anatomia Patologica Lettura magistrale: Pre-Analytic, Quality Control and Predictive Molecular Pathology M. Dietel (Berlin, Germany) Lunch Corso breve Il processo diagnostico nello screening del carcinoma colorettale: dall invio del campione biologico alla refertazione Corso breve La diagnosi dei linfomi cutanei Simposio Dako NON ECM Corso breve Hot topics e controversie in patologia toracica Caffè Slide Seminar Patologia Digestiva LEGENDA = Simposio = Gruppi di Studio Slide Seminar Slide Seminar Dermatopatologia Patologia toracopolmonare = Lettura Magistrale = Corso Breve Simposio Roche NON ECM Il contenzioso medico-paziente Attualità legislative e giurisprudenziali in ambito sanitario = Slide Seminar = Comunicazioni Orali determinazione di fattori predittivi nelle neoplasie del distretto testa-collo Simposio Myriad NON ECM Comunicazioni orali Ematopatologia Comunicazioni orali Patologia Troidea e Neuropatologia Comunicazioni orali Citologia Comunicazioni orali Ginecopatologia e Tecniche = Sessione Congiunta = Assemblea Societaria Martedì 29 Sal Sim Uni mul guid Sim Uni mul guid Lett Nom mia Uno sabi Slid Pato Mercoledì Sala Sim Urop Sim Urop Proc

9 ottiche PROGRAMMA SCIENTIFICO 7 di Sala Cesarea Comunicazioni orali Ematopatologia Comunicazioni orali Patologia Troidea e Neuropatologia Comunicazioni orali Citologia Martedì 29 Ottobre 203 Sala Plenaria Sala Messalia Sala Orange Sala Orange 2 Sala Tarragona Sala Cesarea Simposio I parte Unifocalità, multifocalità e linee guida tumori mammari Simposio Citologia vaginale Simposio Patologia dell Osso Caffè Simposio II parte Unifocalità, multifocalità e linee guida tumori mammari Simposio Nuove Tecniche in citologia Simposio sulla patologia dei Tessuti Molli Patologia Molecolare: le metodologie non in situ Patologia Molecolare: le metodologie in situ Simposio Il patologo cardiovascolare oggi Simposio Il consenso del Gruppo Italiano di Cradiopatologia per la validazione di parametri immunoistochimici nelle cardiomiopatie ereditarie Lettura magistrale: Le cellule staminali tumorali. Ruggero De Maria, Istituto Tumori Regina Elena, Roma Lunch Assemblea Societaria Nomenclatore di Anatomia Patologica - NAP. Uno strumento indispensabile per il patologo Caffè Slide Seminar Patologia mammaria Slide seminar Citologia Slide Seminar Osso e Tessuti Molli La formazione in Anatomia Patologica Comunicazioni orali Patologia Polmonare, Molecolare e Paleopatologia Comunicazioni orali Patologia DIgestiva Comunicazioni orali Patologia Digestiva 2 Comunicazioni orali Dermatopatologia e Patologia Testa-Collo Comunicazioni orali Ginecopatologia e Tecniche ione Congiunta mblea Societaria Mercoledì 30 Ottobre 203 Sala Plenaria Sala Messalia Sala Orange Sala Orange 2 Sala Tarragona Simposio Uropatologia Simposio Neuropatologia SIAPEC-AIOM Caffè Simposio Uropatologia Simposio Neuropatologia SIAPEC-AIOM Sessione AITIC- ANTel-ASSIATEL Sessione AITIC- ANTel-ASSIATEL Proclamazione del nuovo direttivo, consegna dei premi ai migliori Abstracts e chiusura Simposio Patologia dei Trapianti Simposio Patologia dei Trapianti

10 Sommario Relazioni... pag. 47 Comunicazioni orali...» 224 Poster...» 259 Indice degli Autori...» 39

11 Pathologica 203;05: relazioni Domenica, 27 ottobre 203 Sala Plenaria ore Ginecopatologia Simposio: la patologia della cervice uterina Moderatori: G.L. Taddei (Firenze), L. Resta (Bari) Dalla displasia al carcinoma a cellule squamose G.F. Zannoni Anatomia Patologica, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Roma All inizio del secolo scorso il patologo inglese Sir William descrisse la presenza di anomalie cellulari accanto al carcinoma invasivo, mentre fu Brodes che, intorno al 930, introdusse il termine di carcinoma in situ (CIS) per descrivere tali anomalie che identificavano una precancerosi. Soltanto in un secondo momento, tuttavia, Smith e Pemberton dimostrano la relazione temporale e spaziale del carcinoma in situ, descrivendo casi di progressione verso il carcinoma invasivo. Questi studi hanno consentito l identificazione di un modello di screening che permette di riconoscere una lesione preinvasiva da una lesione invasiva. Intorno agli anni 50 Reagan introdusse il termine di displasia per identificare quei quadri cito-istologici con anomalie intermedie rispetto al normale e al carcinoma invasivo e precisamente per descrivere un alterazione della maturazione cellulare caratterizzata dalla proliferazione di cellule squamose del tutto simili a quelle degli strati basali, ma con spiccate alterazioni nucleari e con alterato rapporto nucleo-citoplasma. In base al livello in cui tali alterazioni sono distribuite (strato basale, parabasale e superficiale) la displasia assume il grado rispettivamente di lieve, moderata ed invasiva. Nel frattempo alcuni studi biologici avevano indicato come le alterazioni cellulari della displasia e del carcinoma fossero qualitativamente simili: in entrambe le forme era infatti identificabile una proliferazione monoclonale di cellule epiteliali squamose anormali con contenuto di DNA aneuploide. Sulla base di tali ricerche Richart, introducendo il concetto che tutti i precursori del carcinoma cervicale rappresentino gradi differenti di un unico processo che ha come risultato finale la invasione neoplastica dello stroma, propose la terminologia CIN (neoplasia cervicale intraepiteliale). La CIN è suddivisa in tre categorie: CIN: fase iniziale della malattia con evidenzia delle atipie cellulari nel primo terzo; CIN2: sovrapponibile alla displasia moderata con evidenza di cellule atipiche fino al secondo terzo compreso; CIN3: sovrapponibile alla displasia severa, con cellule atipiche fino allo strato superficiale compreso. Per cellule atipiche si intende allargamento nucleare e atipia nucleare caratterizzata da pleomorfismo, cromatina dispersa a zolle e contorni nucleari irregolari. Molteplici studi condotti negli anni 80 evidenziavano però come la percentuale di CIN che evolveva a carcinoma fosse relativamente bassa (circa 20%), poiché nella maggior parte dei casi la malattia tende a regredire spontaneamente oppure a persistere. Dunque, dal punto di vista biologico, non si può considerare la CIN come una malattia evolutiva ma piuttosto come una malattia biologicamente distinta, più blanda, che nella maggior parte dei casi ha una prognosi eccellente. Tali studi hanno cambiato la storia del trattamento della malattia: attualmente, infatti, il clinico tende a curare soltanto le CIN2 e le CIN 3 mentre tende ad avere un atteggiamento d attesa e conservativo per le CIN. L attuale sistema Betesdha, proposto all inizio degli anni 2000, descrive molto bene lo iato fra le due patologie e il diverso trattamento, dividendo la patologia preneoplastica cervicale in due categorie: la SIL di basso grado designa le coilocitosi e le CIN, mentre le SIL di alto grado designano le CIN2, le CIN3 e il carcinoma in situ. Tale sistema, ideato per la gestione della citologia, trova applicazione anche nell istologia, benché, in tale ultima disciplina risulti preferibile l uso della terminologia CIN. Il motivo risiede nel fatto che, secondo alcuni studi, una quota di CIN2 regredisce, e pertanto il clinico, conoscendo l entità della displasia, può optare per un trattamento più conservativo. Nella nostra istituzione (Policlinico Gemelli) è d uso riportare nel referto la doppia classificazione (esempio: HIGH GRADE SIL CIN2 oppure LOW GRADE SIL CIN). Inoltre si tende a separare, nell ambito delle SIL di basso grado, le coilocitosi e le CIN. La coilocitosi rappresenta l espressione morfologica della infezione da virus HPV e le alterazioni cellulari diagnostiche sono rappresentate dalla presenza di coilociti che possono localizzatasi in tutti e tre gli strati. La lesione CIN richiede la presenza di cellule basaloidi con nucleo ipercromico e talora presenza di attività mitotica. In base alla localizzazione di tali cellule (fino alla strato basale: CIN, fino alla strato parabasale: CIN2 e fino allo strato superficiale: CIN3) si gradua la malattia. In questi anni si è tentato di identificare dei biomarcatori utili a selezionare le CIN con comportamenti evolutivi. Poiché è stato dimostrato che nelle lesioni infettive e in molti CIN il virus dell HPV è in forma episomica, mentre nelle CIN2, CIN3 e carcinomi il virus è in forma integrata, si è pensato di identificare le due forme di infezione, prevedendo un differente intervento. In tal senso ha avuto espansione lo studio di p6, una proteina che esprime l integrazione del Virus, sebbene i risultati clinici abbiano mostrato che la sua positività non è sempre correlabile alla progressione. Numerosi studi concordano nel considerare quale dato maggiormente attendibile la negatività dell espressione per la proteina in base alla constatazione che i casi negativi per p6 tendono a non progredire. Mentre la ricerca del DNA virus ha dato risultati scoraggianti, in quanto il virus viene isolato in molte donne sotto i 30 anni d età, anche in assenza di lesione colposcopicamente rilevabile, più incoraggianti appaiono gli studi sulla identificazione del RNA Virus, che è presente nei casi evolutivi in cui il virus è integrato al DNA dell ospite. Lo studio morfologico della lesione ha un importanza cruciale. A noi patologi, sulla base dell istologia, ci viene richiesto di differenziare le displasie che sono precancerosi da lesioni

12 48 6 Congresso Triennale Siapec-IAP Roma, OTTOBRE 203 simulanti, che hanno un impatto clinico completamente differente: metaplasia squamosa (presenza di glicogeno intracitoplasmatico, nucleo centrale e regolare senza atipie, assenza di disordine di crescita, mantenimento della polarità nucleare, alta espressione di Ki67 prevalentemente nello strato basale e negatività per p6), metaplasia transizionale (donna anziana, associata alla atrofia, assenza di atipie, assenza di mitosi). Il carcinoma invasivo è dunque l evoluzione finale della patologia preinvasiva. Si divide in due grandi categorie, per le quali il clinico adotta comportamenti terapeutici completamente differenti: carcinoma microinvasivo, neoplasia squamosa invasiva per meno di mm 5 ed estendentesi per una lunghezza inferiore a mm 7 (suddisviso im IA: meno di mm 3 e IA2 tra mm 3 e mm 5, IB quando superiore per estensione a mm 7) e carcinoma invasivo, neoplasia invasiva per 5 mm e più. La diagnosi di carcinoma microinvasivo va evitata nelle biopsie e può essere individuata soltanto nelle conizzazioni, avendo avuto cura di includere ed esaminare l intera cervice uterina. Il carcinoma invasivo si gradua in base alle dimensioni nucleari, ma, tra le pur numerose classificazioni proposte, nessuna ha evidenziato correlazione con la prognosi. In genere i carcinomi non chreratinizzanti tendono a rispondere meglio alla radio-chemioterapia rispetto ai carcinomi cheratinizzanti. Il fattore di rischio più importante nella prognosi dei carcinomi radiochemiotrattati rimane tuttavia lo stadio nel momento della diagnosi. Bibliografia Richart RM. Cervical intraepithelial neoplasia: a review. In: Sommer SC, editor. Pathology Annual. Appleton Century Crofts East Norwalk 973, pp Cattani P, Siddu A, D Onghia S, et al. RNA (E6 and E7) assays versus DNA (E6 and E7) assays for risk evaluation for women infected with human papillomavirus. J Clin Microbiol 2009;47: Negri G, Bellisano G, Zannoni GF, et al. p6 ink4a and HPV L immunohistochemistry is helpful for estimating the behavior of low-grade dysplastic lesions of the cervix uteri. Am J Surg Pathol 2008;32: Zannoni GF, Vellone VG, Carbone A. Morphological effects of radiochemotherapy on cervical carcinoma: a morphological study of 50 cases of hysterectomy specimens after neoadjuvant treatment. Int J Gynecol Pathol 2008;27: Tumours of uterine cervix: small cells findings D. Ientile, C. Mignogna, R. Genova UO Anatomia Patologica, Ospedale Buccheri La Ferla FBF, Palermo Current WHO (World Health Organization) classify epithelial tumours of uterine cervix in squamous tumours, glandular tumours, other epithelial tumours and neuroendocrine tumours. Finding a small cells tumour open a range of different diagnosis, ranging over the described classification. Squamous cells tumours were first classified by Wenz and Reagan in large cell keratinizing, large cell nonkeratinizing, and small cell nonkeratinizing; they correlate these forms to the prognostic outcome after radiation therapy. Because the frequent confusion generating among the small cell nonkeratinizing squamous cell carcinoma and small cell undifferentiated carcinomas with neuroendocrine features, WHO classification include the last form in a separate class. Neuroendocrine tumours of uterine cervix are rare, they are classified by WHO as typical (classic) carcinoid tumours, atypical carcinoid tumours, large cell neuroendocrine carcinomas, and small (oat) cell neuroendocrine carcinomas. Small cell neuroendocrine carcinomas account for -6%of cervical carcinomas.. Morphological features are small anaplastic cells with scanty cytoplasm, finely granular chromatin, and inconspicous nucleoli. Mitotic rate is considerable and necrosis is frequent. Vascular involvement is normally present. Small cell neuroendocrine carcinomas should be distinguished from poorly differentiated nonkeratinizing squamous cell carcinomas composed of small cells. Usually nonkeratinizing squamous cell carcinomas have more cytoplasm and cells are arranged in cohesive nests and have nucleoli. Immunohistochemistry for neuroendocrine markers could be useful to distinguish the neuroendocrine nature of the tumour, but not in all cases, because 40% of nonkeratinizing squamous cell carcinomas are positive to neuroendocrine markers and 40% of small cell neuroendocrine carcinomas are positive for cytokeratins. The marker p63 could be helpful to identify squamous differentiation. So in this case it is important to observe the pattern of invasion of the tumour, because nonkeratinizing squamous cell carcinomas colonize the stromal component in discrete nests, whereas small (oat) cell neuroendocrine carcinoma cells invade the stroma diffusely in trabecule and indefined nests. An other area of differential diagnosis are lymphomas involving uterine cervix. The most common type of lymphomas involving the cervix is the diffuse large B-cell lymphoma, followed by the follicular lymphoma. In this cases neoplastic cells infiltrates about, but does not replace or destroy the endocervical glands. Cells are rounded, with nuclear pleomorphism, vescicular chromatin, tiny nucleoli and several mitoses. Immunohistochemical analysis with a screening panel of antibodies against leukocyte common antigen and neuroendocrine markers can easily support the correct diagnosis. Metastatic tumours to the uterine cervix can complicate the differential diagnosis of small (oat) cell neuroendocrine carcinomas. Melanomas and metastatic tumour from the breast can be excluded with immunohistochemistry. Although a careful morphological evaluation can advance the diagnosis. Inflammatory condition as follicular cervicitis could also complicate the diagnosis; the dense infiltrate of lymphocytes present in the stromal component can mimic a small cell tumour, but the presence of prominent follicles and the specific morphology of inflammatory cells, quickly resolve the question. Recent literature highlight the presence of HPV 8 - DNA in neuroendocrine tumours. References World Health Organization Classification of Tumours. Tumours of Breast and Female Genital Organs. Internationale Agency for Research on Cancer. Lyon 2003, p Siriaunkgul S, Utaipat U, Suwiwat S, et al. Prognostic value of HPV8 DNA viral load in patients with early-stage neuroendocrine carcinoma of the uterine cervix. Asian Pac J Cancer Prev 202;3: Abeler VM, Holm R, Nesland JM, et al. Small cell carcinoma of the cervix. A clinicopathologic study of 26 patients. Cancer 994;73:672-7.

13 relazioni 49 Simposio: la diagnostica della biopsia endometriale Moderatori: G.L. Taddei (Firenze), L. Resta (Bari) La biopsia del carcinosarcoma (MMMT) M.L. Carcangiu Roma I carcinosarcomi o tumori mulleriani misti maligni (MMMT) costituiscono < 5% di tutti i tumori maligni dell utero. È stata riscontrata una associazione tra insorgenza del carcinosarcoma e trattamento con Tamoxifen o somministrazione di estrogeni senza l aggiunta di progestinici o trattamento radioterapico pelvico. In questo ultimo caso l intervallo medio tra il trattamento e la comparsa della neoplasia è tra i 0 e 20 anni. Inoltre le pazienti con carcinosarcoma uterino hanno gli stessi fattori di rischio di quelle che sviluppano un carcinoma dell endometrio. C è anche evidenza di una occasionale associazione con mutazioni del gene BRCA e con la sindrome di Lynch. I carcinosarcomi sono tumori tipici delle donne in postmenopausa e il sanguinamento vaginale è la presentazione più frequente. Circa un terzo delle pazienti ha evidenza di neoplasia extrauterina al momento della diagnosi. All esame clinico si apprezza spesso un ingrandimento dell utero o una massa pelvica e la neoplasia è riconoscibile a livello dell ostio cervicale in circa la metà dei casi. Macroscopicamente, i carcinosarcomi appaiono come neoplasie polipoidi, generalmente di grandi dimensioni che riempiono la cavità uterina talvolta prolassando nel canale cervicale. Al taglio la neoplasia è tipicamente soffice e mostra aree di necrosi, emorragia e degenerazione cistica. Inoltre, è frequentemente evidente invasione del miometrio e talvolta estensione alla cervice. Istologicamente, i carcinosarcomi sono caratterizzati da una intima commistione di epitelio e mesenchima, entrambe maligni. Una delle due componenti può predominare. Le due componenti sono di solito distinte e ben demarcate ma possono fondersi l una con l altra. La componente epiteliale è più spesso di tipo endometrioide o sieroso ma possono essere presenti altri tipi istologici. La componente mesenchimale è classificata come omologa quando, come avviene nella maggior parte dei casi, è costituita da un sarcoma di alto grado senza caratteristiche specifiche, ed eterologa quando sono presenti elementi mesenchimali eterologhi come rabdomiosarcoma, condrosarcoma e, raramente, osteosarcoma. Una differenziazione neuroectodermica è stata inoltre descritta. Invasione miometriale e vascolare è un reperto istologico comune. Nelle biopsie o curettage endometriali la diagnosi differenziale tra un carcinosarcoma ed un carcinoma scarsamente differenziato può essere difficile specialmente nei casi in cui la proliferazione neoplastica del carcinoma è costituita da elementi cellulari fusiformi che possono essere interpretati come la componente mesenchimale di una neoplasia bifasica. In genere le cellule fusate sia di tipo squamoso che ghiandolare hanno un grado di atipia citologica inferiore da quello mostrato dalle cellule del carcinosarcoma ed in genere si può osservare una transizione con elementi meglio differenziati. Il riconoscimento di un pattern bifasico, con una ovvia componente sarcomatosa è il più importante criterio per la diagnosi di carcinosarcoma. La presenza di una componente mesenchimale di tipo eterologo ovviamente facilita la diagnosi. Fitogeneticamente, i carcinosarcomi sono ritenuti di derivazione epiteliale ed esemplificano la transizione epiteliomesenchimale. Numerosi studi genetici e molecolari hanno confermato l origine clonale dei carcinosarcomi dimostrando le stesse mutazioni del gene TP53 nella componente epiteliale ed in quella mesenchimale. Le mutazioni più comuni sono TP53 e PIK3CA. Altre alterazioni molecolari a carico di VEGFA, HMGA2 e HPRT sono state recentemente descritte. Le caratteristiche fenotipiche del carcinosarcoma sono state attribuite a cambiamenti nella Akt/beta-catenina pathway ed alla repressione transcrizionale dell E-caderina. I carcinosarcomi hanno una prognosi sfavorevole. Il tipo di diffusione della neoplasia è simile a quello del carcinoma endometriale di alto grado. Una alta proporzione di pazienti con alla presentazione una neoplasia clinicamente stadio uno, all intervento hanno una malattia diffusa al di fuori dell utero. Le metastasi sono tipicamente ai linfonodi pelvici e para-aortici e quelle a distanza al polmone, cervello ed ossa. Tuttavia la maggior parte delle pazienti muore come conseguenza di una recidiva locale/addominale. Il rischio di malattia in uno stadio avanzato è strettamente collegata alla profondità di invasione del miometrio. La presenza di carcinoma di tipo sieroso o a cellule chiare è più frequentemente associata ad altri parametri sfavorevoli. La presenza di elementi eterologhi, specialmente nel caso di una componente tipo rabdomiosarcoma, è statisticamente un fattore associato a cattiva prognosi per le pazienti con un carcinosarcoma stadio I. Bibliografia Djordjevic B, Gien LT, Covens A, et al. Polypoid or non-polypoid? A novel dichotomous approach to uterine carcinosarcoma. Gynecol Oncol 2009;5:32-6. Evans MJ, Langlois NE, Kitchener HC, et al. Is there an association between long-term tamoxifen treatment and the development of carcinosarcoma (malignant mixed Müllerian tumor) of the uterus? Int J Gynecol Cancer. 995;5:30-3. McCluggage WG, Abdulkader M, Price JH, et al. Uterine carcinosarcomas in patients receiving tamoxifen. A report of 9 cases. Int J Gynecol Cancer 2000;0: Kloos I, Delaloge S, Pautier P, et al. Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature. Int J Gynecol Cancer 2002;2: Hubalek M, Ramoni A, Mueller-Holzner E, et al. Malignant mixed mesodermal tumor after tamoxifen therapy for breast cancer. Gynecol Oncol 2004;95: Silverberg SG, Major FJ, Blessing JA, et al. Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol. 990;9:-9. de Brito PA, Silverberg SG, Orenstein JM. Carcinosarcoma (malignant mixed müllerian (mesodermal) tumor) of the female genital tract: immunohistochemical and ultrastructural analysis of 28 cases. Hum Pathol 993;24: D Angelo E, Prat J. Pathology of mixed Müllerian tumours. Best Pract Res Clin Obstet Gynaecol 20;25: Euscher ED, Deavers MT, Lopez-Terrada D, et al. Uterine tumors with neuroectodermal differentiation: a series of 7 cases and review of the literature. Am J Surg Pathol 2008;32: Sreenan JJ, Hart WR. Carcinosarcomas of the female genital tract. A pathologic study of 29 metastatic tumors: further evidence for the dominant role of the epithelial component and the conversion theory of histogenesis. Am J Surg Pathol 995;9: Costa MJ, Guinee D Jr. CD34 immunohistochemistry in female genital tract carcinosarcoma (malignant mixed müllerian tumors) supports a dominant role of the carcinomatous component. Appl Immunohistochem Mol Morphol. 2000;8:293-9.

14 50 6 Congresso Triennale Siapec-IAP Roma, OTTOBRE 203 Yoshida Y, Kurokawa T, Fukuno N, et al. Markers of apoptosis and angiogenesis indicate that carcinomatous components play an important role in the malignant behavior of uterine carcinosarcoma. Hum Pathol 2000;3: Seidman JD, Chauhan S. Evaluation of the relationship between adenosarcoma and carcinosarcoma and a hypothesis of the histogenesis of uterine sarcomas. Int J Gynecol Pathol 2003;22: Szukala SA, Marks JR, Burchette JL, et al. Co-expression of p53 by epithelial and stromal elements in carcinosarcoma of the female genital tract: an immunohistochemical study of 9 cases. Int J Gynecol Cancer. 999;9:3-6. Taylor NP, Zighelboim I, Huettner PC, et al. DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis. Mod Pathol 2006;9: Growdon WB, Roussel BN, Scialabba VL, et al. Tissue-specific signatures of activating PIK3CA and RAS mutations in carcinosarcomas of gynecologic origin. Gynecol Oncol 20;2:22-7. Emoto M, Charnock-Jones DS, Licence DR, et al. Localization of the VEGF and angiopoietin genes in uterine carcinosarcoma. Gynecol Oncol 2004;95: Romero-Pérez L, Castilla MÁ, López-García MÁ, et al. Molecular events in endometrial carcinosarcomas and the role of high mobility group AT-hook 2 in endometrial carcinogenesis. Hum Pathol 203;44: Ferguson SE, Tornos C, Hummer A, et al. Prognostic features of surgical stage I uterine carcinosarcoma. Am J Surg Pathol 2007;3: Sala Massalia ore Ematopatologia Simposio I Moderatori: S. Pileri (Bologna), L. Ruco (Roma) Blastic plasmacytoid dendritic cell neoplasm S.A. Pileri, S.M. Rosaria, F. Fuligni, M.A. Laginestra, C. Agostinelli, T. Makeda 2, L. Pagano 3, A. Pileri Jr 4, N. Pimpinelli 4, L. Cerroni 5, C. Tripodo 6, M. Paulli 7, F. Facchetti 8, C. Croce 9, P.P. Piccaluga Unit of Haematopathology of Bologna University; 2 Division of Haematology of Harvard Medical School, Boston; 3 Institute of Haematology of Catholic University, Rome; 4 Department of Dermatological Sciences of Florence University; 5 Department of Dermatology of Graz University; 6 Tumour Immunology Unit of Palermo University; 7 Anatomic Pathology Section of Pavia University; 8 Department of Pathology of Brescia University; 9 Department of Molecular Virology, Immunology, and Medical Genetics of the Ohio State University Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare neoplasm that is currently included among acute myeloid leukemias (AMLs) [Swerdlow et al., Fourth Edition of the WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, 2008]. It actually represents an orphan disease. This is due to its rarity on the one hand and the clinical aggressiveness and dismal prognosis on the other. For instance, PubMed quotes only 46 papers under the specific item and most of them consist in case reports. About 90% of patients survive no longer than 4 months and no consensus does exist as to the most effective therapeutic approach. On this respect, Pagano et al. (Haematologica 203;98:239-46) have recently reported that acute lymphoblastic leukaemia (ALL)-adjusted schedules might be more effective than the more commonly used AML-like ones. Only a few studies have so far explored the genetics of the tumour by showing a complex karyotype and sporadic genetic alterations. However, these contributions were usually based on small cohorts, thus lacking functional relevance [Petrella et al., AJSP 999;23:37-46; Leroux et al., Blood 2002;99:454-59; Reichard et al., AJSP 2005;29:274-83; Dijkman et al., Blood 2007;09:720-7; Jardin et al., Leukemia 2009;23: ; Wiesner et al., JID 2009;30:52-7; Lucioni et al., Blood 20;8:459-4; Alayed et al., Am J Hematol 203; E-pub ahead of print]. With this in mind, we decided to explore the pathobiology of BPDCN by coordinating an international effort, aiming to enrol: ) a large number of tumours with optimally preserved tissue, possible availability of normal DNA, and complete clinical information, 2) samples of purified normal plasmacytoid dendritic cells, and 3) the CLA- cell line obtained from a BPDCN. The planned approaches included gene expression profiling (GEP), mirna profiling, and next generation sequencing (NGS). Materials and methods Case collection. Stefano A. Pileri, Fabio Facchetti, Lorenzo Cerroni and Marco Paulli critically reviewed the examples of BPDCN collected in the tumour registries of the involved Institutions. Thirty cases were selected that showed optimally preserved formalin-fixed paraffin embedded (FFPE) tissue and almost exclusively consisted of neoplastic cells. In four of these cases, both frozen samples and DNA extracted from normal saliva of the patients were available. In further seven cases, cryopreserved tissue but not saliva was obtained besides FFPE blocks. In all instances, the local Ethical Committee had approved the collection of biological material. Nine samples of normal PDCs were got from the buffy coats of normal donors. Dr. Makeda provided the CAL- cell line. Gene expression profiling studies. Frozen pathological tissue samples and normal PDCs were profiled on the Affymetrix platform according to previous experience (Piccaluga et al., JCI 2007, 7: ). For comparison, public databases were used to obtain the profile of common myeloid precursors (MPs, N = 4), lymphoid precursors (LPs, N = 9), AMLs (N = 32), ALLs (N = 55), resting (N = 2) and activated (N = 2) pdcs. The DASL Whole Genome Assay was used to profile both FFPE and frozen tumour samples, along with normal PDCs and the CAL- cell line on the Illumina HiScanSQ platform as previously reported (Piccaluga et al., JCO 203, E-pub ahead of print). For the latter analysis, the samples were subdivided into a training set and a test, respectively. Micro-RNA expression profiling studies. These were performed by using ncounter mirna Expression Assay Kits (NanoString Technologies, Seattle, WA, USA). Once again, samples were subdivided into a training set and test set. Immunohistochemistry. Validation studies with specific an-

15 relazioni 5 tibodies raised against products of deregulated genes were carried out on automated platforms as previously detailed (Piccaluga et al. JCO 203; E-pub ahead of print). CAL- cell line in vitro experiments. CAL- cells were separately incubated with Bortezomib, Cytarabine (ARA-C) and BMS Cell viability, death and proliferation were measured by Cell Titer-Glo Luminescent Cell Viability Assay, Annexin-V-FLUOS staining kit, and in situ cell proliferation kit FLUOS, respectively. Transfection with mimic. The CAL- cell line was transfected with mimic hsa-mir-720 and negative control. Whole Exome Sequencing (WES). We used the Illumina NGS platform HiScanSQ to carry out a WES study on the BPDCN cases with frozen tissue and normal saliva available in order to identify somatic mutations of diagnostic, prognostic and possibly therapeutic value. The Sanger sequencing technology was used to validate in BPDCN cases the specific genetic mutations found in WES experiments. Bio-informatic analysis. For bio-informatic analyses and result interpretation, we used an integrated approach working in close collaboration with the Center for Computational Biology at New York Columbia University and the Dana Farber Cancer Institute / Harvard University in Boston. Summary of the main results Gene expression profiling studies. For the first time at the molecular level, we definitively recognized the cellular derivation of BPDCN, which turned out to originate from resting PDCs of myeloid origin. Intriguingly, despite the clear myeloid origin, BPDCN did not appear so closely associated to AML, rather presenting an ambiguous molecular profile partially related to both AML and ALL. Based on that, it would be definitely warranted to randomly compare AML-like vs. ALL-treatments. Moreover, we identified in both the training set and test set a molecular signature consisting of 42 genes discriminating between tumors and controls. A careful investigation of these genes provided several insights into the functional alterations of BPDCN, revealing an extensive deregulation of cell adhesion, matrix remodeling, vascular development, and proliferation. Finally, thanks to an integrated bio-informatic approach we discovered aberrant activation of the NF-kB pathway and suggested it as a novel therapeutic target. We tested the efficacy of anti-nf-kb-therapy on the BPDCN cell line, CAL-, and successful evaluated by GEP and IHC the molecular shut-off the NF-kB pathway. In synthesis, we identified for the first time a molecular signature representative of transcriptional abnormalities of BPDCN and developed a cellular model proposing the usage of a novel therapeutic approach in the setting of this otherwise incurable disease. Micro-RNA profiling studies. We identified a signature of 4 discriminant micrornas between BPDCNs and normal PDCs and then, thanks to the integration with GEP data, we recognized a network of mirna - messenger RNA relationships possibly relevant for the tumor patho-biology. In particular, we found in both the training and test set the overexpression of hsa-mir-720, potentially responsible for the constant down-regulation of DAPK2 and ZFHX3, involved in the apoptotic pathway and cell cycle control. To better explore the correlation between has-mir-720 and its putative target genes, we transfected the CAL- cell line with mimic has-mir-720 and after 48 hours measured by Real Time quantitative PCR the expression levels of hsa-mir-720, DAPK2 and ZFHX3. As expected, after transfection, has-mir-720 levels increased while DAPK2 and ZFHX3 expression diminished. WES. WES revealed the presence of DNA mutations associated with myeloid neoplasms. These affected genes notoriously involved in DNA epigenetic modifications and mechanisms of alternative splicing. Interestingly, one patient reported a point mutation of SUZ2 and another one a mutation on ASXL. Both genes belong to the Polycomb-group, responsible for DNA chromatin modifications such as methylation and gene silencing, and have already been found mutated in myeloproliferative and myelodysplastic disorders. Importantly, SUZ2 and ASXL alterations found in BPDCN patients occurred in genomic locations never described before. Both are nonsense mutations presumably resulting in premature stop codons and truncated, usually non-functional protein products. Sanger sequencing confirmed the presence of these mutations in the same cases analyzed by WES. After molecular validation, we decided to extend our investigation to the mutational status of ASXL and SUZ2 as well as of additional 36 well-known myeloid cancer-associated genes in a panel of 30 BPDCNs. To analyze so many genes (each constituted by hundreds of amplicons), we found that the Truseq Custom Amplicon of Illumina was the most appropriate approach. After the design of a personalized assay, preparation of libraries and sequencing run, we are currently analyzing the output data. The relevance of ebv detection in the diagnosis of malignant lymphoma S. Uccini Department of Clinical and Molecular Medicine, Sapienza University of Rome, Ospedale Sant Andrea, Roma, Italy Epstein-Barr virus (EBV), a member of the human herpes virus family, is a linear, double-stranded DNA virus that was initially isolated from a cultured Burkitt lymphoma cell line by Epstein et al. in 964. Subsequent studies have proven that it is causative agent in most cases of infectious mononucleosis. Currently, it is estimated that more than 90% of the adult population worldwide are infected by the virus. Primary infection is usually asymptomatic in childhood, whereas in adolescence or adulthood, it is associated with a selflimiting infectious mononucleosis syndrome in approximately one third of the cases. The virus is secreted in the saliva, and human infection occurs through oral transmission. Oropharyngeal infection results in a lytic (productive) infection followed by infection of circulating B cells, leading to persistence of the viral DNA as an episome in the nucleus, thus establishing latent infection. In lytic infection, EBV-encoded genes selectively replicate virion components including viral DNA genomes and proteins. In latent infection, EBV-encoded genes, which include 6 nuclear antigens (EBNA, 2, 3A, 3B, 3C and LP), 3 latent membrane proteins (LMP, 2A and 2B), 2 small noncoding RNAs (EBER and EBER 2) and BamHI-A rightward transcripts, maintain the existence of the viral genome and enable it to evade immune surveillance. Viral proteins and noncoding RNAs can be easily detected in tissue samples by immunohistochemistry and in situ hybridization. Despite its documented infection of T lymphocytes and epithelial cells in certain circumstances, EBV has a major predilection for B cells because they act as the reservoir for it to persist. Consequently, the persistence of latent EBV genes in B cells results in a carrier state and in certain occasions, transformation into malignant B-cell lymphoma may occur. Because of the preferential infection of B cells, B-cell lymphoma predominate among the EBV-related lymphoproliferative disorders.

16 52 6 Congresso Triennale Siapec-IAP Roma, OTTOBRE 203 According to the World Hearth Organization (WHO) classification of lymphoid tumors, EBV-associated B-cell lymphoproliferative disorders (LPDs) include Hodgkin lymphoma, Burkitt lymphoma, posttransplant lymphoproliferative disorders (PTLDs), lymphomatoid granulomatosis, pyothorax-associated lymphoma and senile EBV-associated B-cell LPDs. Other LPDs, related to the EBV association with T-cell proliferation, are angioimmunoblastic T-cell lymphoma, extranodal nasal type NK/T-cell lymphoma and EBV+ T-cell LPD of childhood. A spectrum of EBV-driven B-cell LPDs occurs in patients with primary immunodeficiency, HIV infection, or with iatrogenic immunosuppression for organ transplantation or autoimmune diseases. Recently, EBV-associated LPDs of the elderly have been described as a wide disease spectrum, with different clinical behaviours, ranging from Japan cases with aggressive behaviour and poor overall survival, to a self-limited clinical condition known as EBV-positive mucocutaneous ulcer. In these conditions, it has been postulated that the immunosenescence and the natural decay of the immune system may represent the underlying pathogenetic events. In conclusion, EBV-associated lymphoma represent a broad spectrum of diseases, with a similar underlying condition represented by an immune defect allowing aggressive viral infection. It has been postulated that immaturity of the immune system in children, HIV-induced or drug-induced immunodeficiency in adults, a senile immunodeficiency in the elderly, represent different but converging events leading to the development of EBV-related LPDs. In this context, the search for EBV-infected cells in tissue sections of LPDs is a necessary requirement for recognition and proper classification of the disease. Corso breve di patologia mammaria: lesioni benigne che simulano la malignità e viceversa Moderatori: V. Eusebi (Bologna), A. Sapino (Torino) Benign locally infiltrating neoplasm of the nipple with malignant clinical presentation E. Bonanno, M. Scimeca, M. Chimenti Università di Roma Tor Vergata, Fondazione Policlinico Tor Vergata, Dipartimento di Biomedicina e Prevenzione, Roma Clinical Presentation. A 65-year-old woman with 2 months history of inversion, retraction and congestion of nipple of the right breast. Any significant history of breast diseases was referred. No risk factors were identified for breast cancer except late age at first delivery. Physical examination revealed a firm discrete mass, about 3 centimeters large in the right nipple. Mammography confirmed the presence of a ill-defined and high-density tumor with retraction of peripheral parenchimal areas. Echography revealed a speculated nodule with indistinct margins and with a vascular pole in the center of the lesion and two additional more lesions, respectively 0,5 and 0,8 cm in diameter with similar characteristics in QSE of the same breast. One axillary lymph node (2 cm in diameter) was clinically and radiologically evident and suspected for metastasis. Any relevant finding in the controlateral breast. Cytopathology and Histology. The cytological analysis of the lesion, performed by thin layer cytology, showed few aggregates of epithelial duct cells sometimes with cytoplasmic vacuolization and focal nuclear irregularity. A needle biopsy of the lesion was requested. Due to the malignant clinical presentation of the lesion the patient accepted a mastectomy with nodes dissection. Gross examination of the breast revealed the presence of multiple ill-defined firm gray nodules diffused to all breast lumps. On microscopic examination the lesions were formed by ductules, tubules and strands of small uniform cells infiltrating the surrounding tissue. Some ducts showed a characteristic comma-shape. Cells showed nuclear pleomorphism, hyperchromasia. Mitotic activity was absent. Small keratinous cysts containing well-developed lamellar keratin and bland appearance of cubic cell lining gland lumina were also reported. Immunohistochemical markers for myoepithelial layer such as smooth muscle antigen, p63 and calponin were positive; inner layer s cells were positive for CK5 and CK4 whereas CK7 and oestrogen receptor were negative. Isolated foci of ductal carcinoma in situ (cribriform and one only focus of comedonic type) 3 mm in diameter associated with ductal papillomatosis were found at the side of the main lesion. Axillary lymph nodes were negative for metastasis. The morphological findings of the lesions were consistent with syringomatous adenoma of the nipple. The presence of double layer provided additional evidence in favor of syringomatous tumour. No recurrence had occurred in five years of follow-up. Discussion and Conclusions. The term syringomatous adenoma of the nipple was first coined by Rosen in 983. Jones et al. 2, in a clinical and pathological study of cases in 989, introduced the term infiltrating to emphasize the locally infiltrative nature of this benign but peculiar lesion. The WHO classification 202 repost the termo f Syngomatous tumour 3. The histological derication of these lesions has been a matter of debate; the epidermis covering the nipple, lactiferous duct, and sweat gland ducts have all been postulated ad possible sites of origin. Patients with syngomatous adenoma of the nipple have been reported to range in age from -76 years with an average age of 40 years 4. The clinical presentation of infiltrating suringomatous adenoma of the nipple is variable. There is no specidic radiological features characheristic to this unusual condition. A clearer under standing of the spectrum of breast lesions with syringomatous features will no doubt benefit both patients and pathologists alike. It is important to differenziate syringomatous adenoma from tubular carcinoma and low-grade adenosquamous carcinoma 5. The glandular structures of tubular carcinoma are mostly angolate with open lumina and are composed of single cell population as opposed to syringomatous adenoma, which has variable amount of squamous metaplasia and has characteristic comma or tad pole shapes. Ductal carcinoma in situ is often associated with tubular carcinoma 6. Surgical management varied from excisional biopsy to radical mastectomy although mastectomy is not indicated as primary treatment. Local recurrence has been attributed to be related to incomplete excision. Axillary dissection is not

17 relazioni 53 requie since any nodal metastasis has been found in patients who had axillary dissection. Distant metastasis is unknown with syringomatous adenoma on follow-up of as long as 24 years. Complete excision with free margins seems to be an appropriate therapy and extensive surgical procedures should be avoided. Due to the rarity of this disease, long-term followup is necessary. Benign mesenchimal tumor mimicking a carcinoma. Clinical presentation. A 60 years-old woman undergoes her first mammography for screening. An hyperdense spiculated lesion with ill defined margins was found in the upper quadrants of right breast, near to chest muscle layer. Ultrasounds examintion showed an hypoecogenic mass, with irregular margins (,47 cm of axial diameter). A magnetic resonance examination was performed to evaluate the presence of multiple foci and to evaluate, in preoperative assessment, the local extent to the pectoralis fascia. It depicts a nodular area, hypointense, with speckled and irregular margins (,5 cm of axial diameter). Cytopathology and Histology. Cytological smear was characterized by scant cellularity, with medium to large size and polygonal elements, single or in small group with large, eosinophilic and granular cytoplasm and with uniform, round to oval nuclei. Cell lacked of significant atypia or mitosis. A needle biopsy of the lesion was requested. Patient refused a core-biopsy, therefore an excissional surgical biopsy was performed. In the lumpectomy a 2 cm firm, homogeneous greyish yellow mass, with ill-defined margins, fixed to the fascia was described. Frozen sections showed a neoplasia with large cells in sheets and cords with a clear infiltrative pattern. Cells showed numerous fine granules and scattered eosinophilic globules in the cytoplasm; any nuclear atypia or mitotic activity was observed. Exicision margins were free from neoplasia. Despite the infiltrative pattern of the muscle due to the absence of cellular atypia a conservative surgery was suggested and the diagnosis was deferred to the paraffin embedded tissue. The examination of the formalin fixed, paraffin embedded tissue confirmed the presence of a neoplasia made by large eosinophilic polygonal cells with well defined cell borders, granular cytoplasm, bland nuclei and infiltrative pattern of growth. Histochemical study demonstrated that the cytoplasmic granules contained PAS positive and diastase resistant material. The immunohistochemistry revealed a positivity for S-00 protein and CD68 antigen a week and focal positivity for CEA antin and Vimentin; cytokeratins and GFAP were negative. The evaluation of Ki67 prolifetive antigen was low (< 0%). A final diagnosis of granular cell tumours (GCT) was formulated. Any additional surgery was performed. No recurrence had occurred in three years of follow-up. Discussion and Conclusions. Granular cell tumour (GCT) it s a mesenchymal tumour that was first described in the breast by Abrikossof in GCT occur throughout the body with about 5% of them originating in the breast. With very rare exceptions GCT is a benign neoplasm. Many authors 8- emphasize the importance of distinguish this benign tumour from carcinoma. Granular cell are rare lesions of probable Schwann cell origin, which can occur in a variety of visceral and cutaneous sites 2. The most common site is in the tongue, but they are present in the breast around 6-8% of cases. GCT can occurs more commonly in pre-menopausal woman. Clinically they present as a mass, which may mimic malignancy if there is overlying skin tethering. In contrast to other breast tumours, which occur predominantly in the upper outer quadrant, GCT occur most commonly in the upper inner quadrant corresponding to the cutaneous sensory territory of the supraclavicular nerve. Synoptic table for Granular cells tumors. Age 7-74 Clinical Firm, hard, painless mass. Occur most commonly in the upper inner quadrant. Radiological Stellate mass lacking calcifications (suggestive for carcinoma). Rarely well circumscribed Cytological There could be a incongruity with clinical-radiological findings: tumour s cells may be mistaken for foamy macrophages or typical or atypical apocrine cells. Histology - Medium-large size cells with granular, eosinophilic, PAS-positive cytoplasm - Uniform round to oval nuclei with sometimes prominent nucleoli - Infiltrative growth pattern - Collagenous stroma - Mitosis or necrosis very rare - No significant pleomorphism, with rare exceptions Immunophenotype Positive markers: S00, CD68, CEA (focal), VIM (focal) Negative markers: panck, ER, PR, CerbB2, GFAP Prognosis Excellent. Though non-metastasizing, it may recur locally if incompletely excised. Malignant GCT is very rare (<%) and prognosis in this case is very poor. Feature suggestive of malignancy include large tumour size, pleomorphism, increased mitotic activity, necrosis. DIFFERENTIAL DIAGNOSIS CLUES Apocrine carcinoma Intraductal carcinoma, nuclear pleomorphism; panck+, S00- Histiocytoid carcinoma (breast) GCDFP+, panck+, EMA+, S00- Alveolar soft part sarcoma Metastasis (kidney) WHEN SUSPECT A GRANULA CELL TUMORS (GCT) Regular nests of cell, variable granularity, S00 variable. CD0+, VIM+. - Polygonal cell with granular and eosinophilic cytoplasm - Infiltrative pattern lacking cellular atypia and pleomorphism - Immunophenotypic definition

18 54 6 Congresso Triennale Siapec-IAP Roma, OTTOBRE 203 Multiplicity of lesions can be observed, particularly in black patients. GCT can simulate carcinoma because of its firm consistency, clinically in the breast adhesion to the pectoralis fascia, and skin retraction. Some GCTs appear as an illdefined or stellate lesion on mammograms, which strengthens the clinical impression of carcinoma 3. GCTs must be distinguished from breast cancer, especially from apocrine carcinomas and the histiocytic variant of invasive lobular carcinoma, histiocytic lesions, and metastic disease. Immunoreactivity for S-00 protein, CEA, and vimentin, with a negative reaction against cytokeratin are indicative od GCT. Treatment of GCT is wide local resection 4. The granular cell tumour is almost always benign. A malignant type is, however, encountered in 2% of the cases. Even thug malignant, this tumour rarely metastatizes. It responds poorly to chemotherapy and radiation therapy. Because there is a tendency for local recurrence and the remote possibilty of distant metastasis, follow-up is a crucial aspect of treatment and management. The local recurrence rate of benign granular cell breast tumour ranges between 2% and 8%, while the recurrence rate for malignant form is much higher, at around 35%. Local recurrence is typically rapid, however, usually within year of the original surgery 5. Distant metastasis of malignant granular cell breast tumors i suite high, at just over 60%. References Rosen PP. Syringomatous adenoma of the nipple. Am J Surg Pathol 983;7: Jones MW, Norris HJ, Snyder RC. Infiltrating syringomatous adenoma of the nipple. A clinical and pathological study of cases. Am J Surg Pathol 989;3: Eusebi, Lester. Syringomatous tumor in WHO Classification of tumours of the breast 202;5. 4 Carter E, Dyess DL. Infiltrating syringomatous adenoma of the nipple: a case report and 20-year retrospective review. Breast J 2004;0: Rosen PP, Ernsberger D. Low-grade adenosquamous carcinoma. A variant of metaplastic mammary carcinoma. Am J Surg Pathol 987;: Rosen PP, Caicco JA. Florid papollomatosis of the nipple. A study of 5 patients, including nine with mammary carcinoma. Am J Surg Pathol 986;0: Abrikossoff A. Uber Myome, ausgehend von der quergestreiften wilkuerlichen muskulatur. Virchows Arch Pathol Anat 926;260: Delaloye F, Seraj F, Guillou L, et al. Granular cell tumor of the breast: a diagnostic pitfall. Breast 2002;: Haangensen CD, Purdy Stout A. Granular cell myoblastome of the mammary gland. Ann Surg 946;24: Lelle RJ, Park H, Brow CA. Benign granular cell tumor mimicking carcinoma of the breast. Report of the case. Eur J Gynaecol oncol 992;3: Adeniran A, Al-Ahmadie H, Mahoney MC, et al. Granular cell tumor of the breast: a series of 7 cases and review of the literature. Breast J 2004;0: Adeniran A, Al-Ahmadie H, Mahoney MC, et al. Granular cell tumor of the breast: a series of 7 cases and review of the literature. Breast J 2002;0: Delaloye F, Seraj F, Guillou L, et al. Granular cell rumor of the breast: a diagnostic pitfall. Breast 2002;: Aneiros-Fernandex J, Arias-Santiago S, Husein-ElAhmed H, et al. Cutaneous granular cell tumor of the breast: a clinical diagnostic pitfall. J Clin Med Res 200;2: Brown SC, Audisio RA, Regitnig P. Granular cell tumour of the breast. Surg Oncol 20;20: Background. Multinucleated stromal giant cells (MSGC) in breast tissue were reported for the first time by Rosen in 979. The author described the presence of these cells both in normal and tumoral tissues, concluding that they had no clinical value. Moreover, he suggested they might have a reparative nature, being often found at the periphery of mammary carcinomas. Among breast lesions, fibroadenoma is labeled as a fibro-epithelial tumor, consisting of a stromal component commingled with an epithelial component, hence the term biphasic lesion. In spite of the high breast incidence of fibro-epithelial tumors, MSGC are only rarely observed inside these neoplasms 2 3. Therefore, the histopathological detection of these cells in a fibroadenoma can render difficult the diagnostic framing, by placing the suspicion of malignancy. Methods. A 40 years old woman presented with a new selfpalpable right breast nodule. After preliminary evaluation by ultrasound and mammography, she underwent surgical nodulectomy. The patient s post-surgical recovery was uneventful. Thirty months after simple excision, the patient remained free of disease recurrence. On gross examination, the grayish firm nodule measured 2.7 cm in diameter and was characterized by expansive borders. The specimen was routinely processed for histopathological examination (4% formaldehyde fixation, paraffin embedding, sections staining with hematoxylineosin). Immunohistochemistry for CD34 (Ventana) and p53 (Ventana) was performed using a streptavidin-biotin peroxidase method. Results. Microscopically, the nodule appeared to be biphasic in nature. The epithelial component consisted of compressed glands and haphazardly-arranged ducts, lined by benign epithelial cells and surrounded by abundant stroma. In some areas of the stromal component, an increased mitotic activity (Fig. ) with isolated atypical mitotic figures and scattered giant cells were noticeable (Fig. 2). Some giant cells exhibited multiple nuclei (up to 5) with fine chromatin and sporadic small nucleoli. Giant cells were found to be immunoreactive for CD34 and p53. Based on morphologic features, a diagnosis of fibroadenoma with MSGC was rendered. Discussion. The histopathological finding of MSGT in fibroadenoma is a rare occurrence 4. The large size (up to 00 um), coupled with the occasional bizarre appearance, of these cells may alarm the pathologist, but so far there is consensus about their benign biological behavior 5. The increased mitotic activity and the isolated atypical mitotic figures in MGST do Fig.. Increased mitotic activity in the stroma, HE, x240 (original magnification). Fig. 2. Multinucleated giant cells scattered in the stroma, HE, x200 (original magnification). Breast fibroadenoma containing multinucleated stromal giant cells L. Roncati, G. Ficarra, A. Maiorana Department of Diagnostic, Clinical Medicine and Public Health, section of Pathology, University of Modena and Reggio Emilia, Modena, Italy

19 relazioni 55 not correlate with malignancy and they should not influence the tumor grading. In fact, also our follow-up data support that the detection of MGST in a fibroadenoma has no adverse clinical outcome. The differential diagnosis arises with a benign, borderline or malignant phyllodes tumor containing giant cells or with a primitive pleomorphic sarcoma of the breast. The greatest attention should be reserved to a benign phyllodes tumor with MGST 6 : the presence of long epitheliallined clefts and of pseudoangiomatous stromal changes are in favour of a phyllodes tumor. In the differential diagnostic path, the absence of clear epithelial atypias allows to exclude a carcinomatous component, while the limited number of pleomorphic stromal cells in a biphasic context permits to exclude pleomorphic sarcoma. A single case of MSGC in adenoid cystic carcinoma has been reported in the literature 7. Although normal breast stroma, like most collagenous connective tissues, contains CD34+ resident dendritic interstitial cells, the histogenesis of MSGCs in fibro-epithelial tumors still remains obscure, even if they appear reactive in nature. According to their immunohistochemical profile (vimentin+, CD34+, p53+) and the results obtained by electron microscopy, a mesenchymal derivation (fibroblastic, myofibroblastic or fibrohistiocytic) seems to be the most plausible origin 8. References Rosen PP. Multinucleated mammary stromal giant cells. Cancer 979;44: Powell CM, Cranor ML, Rosen PP. Multinucleated stromal giant cells in mammary fibroepithelial neoplasms. A study of patients. Arch Pathol Lab Med 994;8: Ryska A, Reynolds C, Keeney GL. Benign tumors of the breast with multinucleated stromal giant cells. Immunohistochemical analysis of six cases and review of the literature. Virchows Arch 200;439: Berean K, Tron VA, Churg A, et al. Mammary fibroadenoma with multinucleated stromal giant cells. Am J Surg Pathol 986;0: Huo L, Gilcrease MZ. Fibroepithelial lesions of the breast with pleomorphic stromal giant cells: a clinicopathologic study of 4 cases and review of the literature. Ann Diagn Pathol 2009;3: Tse GM, Law BK, Chan KF, et al. Multinucleated stromal giant cells in mammary phyllodes tumours. Pathology 200;33: Milentijević MJ, Basić M, Petrović A. Multinucleated stromal giant cells in adenoid cystic carcinoma of the breast: a case report and literature review. Vojnosanit Pregl 20;68: Silverman JS, Tamsen A. Mammary fibroadenoma and some phyllodes tumour stroma are composed of CD34+ fibroblasts and factor XIIIa+ dendrophages. Histopathology 996;29:4-9. Tubular carcinoma of the breast in collision with radial scar L. Roncati, G. Ficarra, A. Maiorana Department of Diagnostic, Clinical Medicine and Public Health, section of Pathology, University of Modena and Reggio Emilia, Modena, Italy Background. Radial scars are stellate lesions characterized by a sclero-elastotic center, that contains distorted tubular structures lined by hyperplastic epithelium. A rosette-like arrangement (zoning phenomenon) is usually detected. Radial scar was described for the first time by Hamperl in 975 and it is characterized by several synonyms, which by themselves describe its nature, such as benign scleroelastotic lesion and radial sclerosing lesion. Its biological behaviour has been extensively discussed by many authors with conflicting points of view 2. It has also been argued that it could reflect a pre-neoplastic condition towards the development of tubular carcinoma 3. Tubular carcinoma is a low-grade invasive carcinoma consisting of a variable number of tubules with open lumens lined by a single layer of monotonous cells. Its incidence is approximately 5% of all breast cancers 4. Patients affected by tubular carcinoma have usually a good prognosis, particularly when tumor size is less than cm. Methods. A 56 years old woman underwent a routine mammography that revealed the presence of a radial thickening of approximately cm localized at the supero-medial quadrant of left breast. FNAC showed hyperplastic cells and an isolated cellular cluster exhibiting mild nuclear atypia and lack of myoepithelial cells (C). Subsequently, vacuum-assisted core biopsy was performed. Quadrantectomy and removal of the sentinel lymph node were performed two months later. All bioptic and surgical specimens were routinely processed for histopathological examination (4% formaldehyde fixation, paraffin embedding, sections staining with hematoxylineosin). Immunohistochemistry for p63 (Ventana) and miosin (Ventana) was also performed using a streptavidin-biotin peroxidase method. Results. At microscopic examination, isolated tubules lined by a single layer of monotonous epithelial cells with apical snouts (Fig. ), but devoid of myoepithelial cells, were detected adjacent to a sclero-elastotic parenchymal lesion (Fig. 2). The absence of myoepithelial cells in tubules was confirmed by immunohistochemistry (Fig. 3) and a diagnosis of tubular carcinoma of the breast arising in a radial scar was rendered. Pathological examination of the quadrantectomy specimen confirmed the presence of remnants of a small tubular carcinoma. In the remaing tissue, isolated microcalcifications and a minute in situ ductal carcinoma were also observed. The sentinel lymph node was negative. Discussion. In the breast, the collision of a carcinoma of low-grade malignancy with a carcinoma-mimicker is a pos- Fig.. Focus of tubular structures lined by a single layer of monotonous epithelial cells, HE, x50 (original magnification). Fig. 2. Area with a scleroelastotic lesion, HE, x00 (original magnification). Fig. 3. Neoplastic tubules lacking myoepithelial cell layer (a non-neoplastic tubule with myoepithelial cells can be seen on the right), immunohistochemistry for p63, x250 (original magnification).

20 56 6 Congresso Triennale Siapec-IAP Roma, OTTOBRE 203 sible occurrence: the challenge is to recognize both entities by placing them in the differential diagnosis with other similar diseases. In such cases, it becomes fundamental to have a well-represented bioptic sample, as well as an immunohistochemical aid. The occurrence of a tubular carcinoma in a radial scar offers a pathogenic cue: on the one side the two lesions can be regarded as separate entities, while, on the other side, a continuum from benignancy to malignancy might be seen. In tubular carcinoma, tubules are lined by a single layer of cuboidal to columnar cells with round nuclei and small nucleoli; mitoses are uncommon. Tubules are devoid of myoepithelial cells and the neoplastic cells stain for cytokeratins and E- cadherin 5. The differential diagnosis involves tubulolobular carcinoma, low-grade adenosquamous (syringoid) carcinoma, micro-glandular adenosis and the pure scleroelastotic lesion (radial scar). Tubulolobular carcinoma can be quickly recognized because it combines the morphological features and the immunohistochemical profile of both tubular carcinoma and invasive lobular carcinoma 6. In the low-grade adenosquamous (syringoid) carcinoma, the comma-shaped tubular structures present variable squamoid differentiation and are lined at least by a double cell layer, the outer being often actin rich 7. The presence of small quite uniform glands, invested by a thin basal lamina and positive for S00 protein, is instead typical for micro-glandular adenosis 8. In all benign scleroelastotic lesions, ducts are encircled by myoepithelial cells, well ascertainable by immunohistochemistry. At low magnification, radial scar shows a central hyaline core with compressed tubules from which hyperplastic ducts radiate in a stellate configuration 9. This typical architecture and the presence of myoepithelial cells in tubules, together with a circumferential basement membrane, are absent in tubular carcinoma. On the contrary, in duct ectasia, the duct are not compressed but dilatated, with periductal inflammation and progressive fibrotic changes 0. References Hamperl H. Strahlige narben und obliterierende mastopathie. Virchows Arch A Pathol Anat Histopathol 975;369: Jacobs TW, Byrne C, Colditz G, et al. Radial scars in benign breastbiopsy specimens and the risk of breast cancer. N Engl J Med 999;340: Manfrin E, Remo A, Falsipollo F, et al. Risk of neoplastic transformation in asymptomatic radial scar. Analysis of 7 cases. Breast Cancer Res Treat 2008;07: Carstens PH, Greenberg RA, Francis D, et al. Tubular carcinoma of the breast. A long term follow-up. Histopathology 985;9: Deos PH, Norris HJ. Well-differentiated (tubular) carcinoma of the breast. A clinicopathologic study of 45 pure and mixed cases. Am J Clin Pathol 982;78:-7. 6 Wheeler DT, Tai LH, Brathauer GL, et al. Tubulolobular carcinoma of the breast: an analysis of 27 cases of a tumor with a hybrid morphology and immunoprofile. Am J Surg Pathol 2004;28: Soo K, Tan PH. Low-grade adenosquamous carcinoma of the breast. J Clin Pathol 203;66: Koenig C, Dadmanesh F, Bratthauer GL, et al. Carcinoma arising in microglandular adenosis: an immunohistochemical analysis of 20 intraepithelial and invasive neoplasms. Int J Surg Pathol 2000;8: Alvarado-Cabrero I, Tavassoli PA. Neoplastic and malignant lesions involving or arising in a radial scar: a clinicopathologic analysis of 7 cases. Breast J 2000;6: Dixon JM, Ravisekar O, Chetty U, et al. Periductal mastitis and duct ectasia: different conditions with different etiologies. Br J Surg 996;83: Sala Orange ore Patologia endocrina Intermediate and high grade endocrine/neuroendocrine neoplasms: state of the art Moderatori: M. Papotti (Torino), S. La Rosa (Varese) Thyroid F. Basolo Pisa Thyroid carcinomas account for less than % of all human tumors with an annual incidence varies in different parts of the world, from 0.5 to 0 cases per 00,000 population. The papillary carcinoma (PTC) is the most frequent form of thyroid cancer, with a range between 80 and 90% of all thyroid tumors. The prognosis of PTC is usually good with a 0-year survival greater than 90%. However, 0% of patients with PTC died of complications of the disease. Over the years able to predict the worst prognosis parameters have been identified. Among these we include the age, gender, presence of extrathyroidal tissue infiltration, nodal and distant metastasis, histological variants, the size of the tumor. In addition to these factors have recently been highlighted genetic factors can affect the prognosis of PTC. First of all the gene mutation in BRAF can influence tumor progression in terms of infiltration of extrathyroidal tissues and lymph node and distance metastasis. Rarer tumors but surely with worse prognosis are the medullary carcinomas, which account for approximately 0% of malignant thyroid tumors. Originated by C-cells, have a typical clinical presentation, often familiarity and association with other neuroendocrine disorders. To date it is the only thyroid cancer that recognizes C cell hyperplasia like a possible precursor. Most medullary carcinomas are sporadic, however there is a proportion, about 20%, of familial cases that may be associated with multiple endocrine syndromes and which presents the RET proto-oncogene mutations. The anaplastic thyroid carcinoma, although rare (5-0% of thyroid carcinomas), is one of the more aggressive tumors in humans. It generally occurs in patients of advanced age as massive fast-growing masses and, clinically, patients with anaplastic carcinoma reach the exitus in a few months due to massive local infiltration and distant metastases. Microscopically is a very heterogeneous tumor presenting epithelioid,


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