2 pathologica 2007;99: Caso clinico Carcinoma dei dotti collettori di Bellini in età pediatrica: descrizione di un caso e revisione della letteratura Collecting duct carcinoma iin paediatric patients: a case report and review of the literature A. Gurrera, P. Amico, A. Di Cataldo *, E. Vasquez, G. Magro Dip. G.F. Ingrassia, Anatomia Patologica, Azienda Ospedaliero-Universitaria Policlinico Gaspare Rodolico, Catania; * Centro di Riferimento Ematologia e Oncologia Pediatrica, Azienda Ospedaliero-Universitaria Policlinico Gaspare Rodolico, Catania Parole chiave Carcinoma dotti collettori Rene Età pediatrica Key words Collecting duct carcinoma Kidney Children Riassunto Il carcinoma dei dotti collettori è una variante rara di carcinoma renale che insorge in pazienti più giovani rispetto al carcinoma renale convenzionale. È caratterizzato da un decorso clinico aggressivo, spesso fatale. I carcinomi renali dell età pediatrica sono rari e si associano spesso a specifiche alterazioni genetiche. Gli istotipi più frequenti sono il carcinoma a cellule chiare e quello a cellule cromofobe, mentre eccezionale è il riscontro del carcinoma dei dotti collettori, con circa 8 casi riportati in letteratura. Descriviamo gli aspetti clinico-patologici di un carcinoma dei dotti collettori insorto in un bambino di 11 anni caratterizzato da un decorso clinico fatale. Summary Collecting duct carcinoma is an uncommon variant of renal cell carcinoma that usually occurs at an earlier age compared to conventional renal cell carcinoma. It is characterised by an aggressive, often fatal, course. Renal cell carcinoma rarely occurs in paediatric patients, and is almost always in association with specific genetic alterations; the most common histotypes are the clear cell and chromophobe cell variants. Collecting duct carcinoma is rare, and only 8 cases have been reported in the literature. The authors describe the clinico-pathological features of a fatal collecting duct carcinoma in an 11-year old boy. Introduzione Il carcinoma dei dotti collettori di Bellini è una rara neoplasia renale, rappresentando meno dell 1% dei tumori epiteliali maligni dell adulto. Questo tumore mostra un picco d incidenza attorno ai 50 anni di età, e generalmente si riscontra in pazienti di età più giovane rispetto al carcinoma renale convenzionale 1 2. La distinzione di questa neoplasia dagli altri istotipi di carcinoma renale è di cruciale importanza, in quanto presenta un decorso clinico aggressivo ed una prognosi sfavorevole. Infatti, nella maggior parte dei casi, al momento della diagnosi, la neoplasia si presenta già in fase metastatica 1 2. Sono eccezionali i casi di carcinoma dei dotti collettori di Bellini insorti in età pediatrica o adolescenziale; in letteratura finora sono stati descritti circa otto casi. Caso clinico Un bambino di 11 anni presentava improvvisamente, in pieno benessere, un episodio di ematuria macroscopica. L esame obiettivo e gli esami ematochimici risultavano nella norma. L ecografia dell addome evidenziava la presenza di una neoformazione solida nel rene destro. La TC toraco-addominale confermava la presenza di una neoformazione renale, infiltrante il grasso perirenale con aree ipodense riferibili ad aree di necrosi intralesionale. Inoltre, si evidenziavano trombosi della vena cava inferiore ed alcuni linfonodi aumentati di volume (diametro massimo 14 mm) in sede inter-aorto-cavale. Era presente una lesione nel VII segmento epatico, di verosimile origine metastatica. Il bambino veniva sottoposto a nefrectomia radicale destra con linfoadenectomia. Macroscopicamente la neoplasia, delle dimensioni Corrispondenza Dott.ssa Alessandra Gurrera, Dip. G.F. Ingrassia, Anatomia Patologica, Azienda Ospedaliero-Universitaria Policlinico Gaspare Rodolico, via S. Sofia 87, Catania, Italy - Tel Fax
3 302 A. Gurrera et al. di 6,3 cm di diametro maggiore, era localizzata nel polo superiore del rene destro e occupava sia la corticale che la midollare. Alla superficie di taglio, la neoformazione presentava un colorito bianco-grigiastro, ampie aree di necrosi e margini infiltrativi (Fig. 1). La capsula renale, a tratti, appariva infiltrata. I linfonodi reperiti nel tessuto adiposo ilare e quelli addominali para-aortici asportati, apparivano aumentati di volume e conglobati. Istologicamente la neoplasia presentava un pattern prevalentemente tubulare (Fig. 2A), con tubuli di varie dimensioni, talora dilatati microcisticamente, immersi in uno stroma con marcata reazione desmoplastica (Fig. 2B). Erano presenti focali accumuli di mucina intraluminale. I tubuli erano rivestiti da cellule cubico/colonnari con abbondante citoplasma eosinofilo che, occasionalmente, protrudevano all interno del lume, configurando un aspetto tipo hobnail. Si riscontravano, inoltre, aree con pattern di crescita di tipo solido-trabecolare (Fig. 2C), con focale aspetto fusato-sarcomatoide ed ampie aree di necrosi tumorale. Le cellule mostravano marcato pleomorfismo nucleare con nuclei vescicolosi e Fig. 1. Aspetto macroscopico. Neoformazione solida in corrispondenza del polo superiore del rene destro, con margini irregolari ed aree di necrosi intratumorale. Fig. 2. Aspetti microscopici. (A) Pattern di crescita tubulare: tubuli neoplastici di varie dimensioni, immersi in stroma desmoplastico. (B) Tubuli neoplastici dilatati microcisticamente con reazione desmoplastica dello stroma. (C) Pattern di crescita prevalentemente solidotrabecolare. (D) Tubuli circostanti la neoplasia con displasia di grado variabile, da lieve a moderato-severo con associata neoplasia invasiva (in basso a destra). A B C D
4 Carcinoma dei dotti collettori di Bellini in età pediatrica 303 nucleoli prominenti; si evidenziavano numerose mitosi, alcune atipiche. Alcuni tubuli circostanti alla neoplasia presentavano un grado variabile di displasia, da lieve a moderato-severo (Fig. 2D). Sulla base degli aspetti morfologici veniva posta la diagnosi di carcinoma dei dotti collettori di Bellini, di tipo classico. La neoplasia infiltrava la pelvi e si estendeva al tessuto adiposo del seno renale e perirenale. Tutti i linfonodi esaminati risultavano metastatici. Stadiazione ptnm: T3 N2 Mx. Le indagini immunoistochimiche evidenziarono una positività per l antigene epiteliale di membrana (EMA), per le citocheratine 7, 8, 18 e per le citocheratine ad alto peso (34βE12). Negative risultarono le colorazioni per vimentina e racemasi (Tab. I). Tab. I. Carcinoma dei dotti collettori in età pediatrica: dati immunoistochimici ottenuti. Citocheratina 7 + Citocheratina 8 + Citocheratina 18 + Citocheratina 34βE12 + Antigene epiteliale di membrana + Racemasi - Vimentina - Per il carcinoma dei dotti collettori di Bellini, patologia estremamente rara in età pediatrica, non è disponibile un protocollo terapeutico standard. Le Linee Guida del Gruppo TREP (Tumori Rari Età Pediatrica) dell AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) prevedono, in caso di nefrectomia e presenza di linfonodi metastatici, un trattamento con Interleuchina 2 alla dose di di Unità/mq/die per via sottocutanea per 5 giorni, seguiti da 9 giorni di pausa, per un periodo di 6 mesi, quindi un totale di 12 cicli. In assenza di effetti collaterali significativi è previsto di aumentare il dosaggio fino a di Unità. La terapia è stata somministrata per i primi 7 cicli senza problemi di rilievo, all infuori di una lieve sindrome influenzale trattata efficacemente con FANS. All inizio dell 8 ciclo, una ecografia dell addome mostrava la presenza di numerosi linfonodi aumentati di volume in prossimità del tripode celiaco. La TC confermava il dato ecografico e mostrava altresì: i) linfonodi aumentati di volume nel mediastino anteriore, medio e posteriore ed agli ili polmonari; ii) diffuse metastasi polmonari bilaterali; iii) metastasi ossee al rachide toraco-lombare, e alle due scapole; iv) numerose metastasi epatiche; v) trombosi della vena cava inferiore allo sbocco della vena renale ed a livello intraepatico; vi) metastasi al surrene sinistro; vi) metastasi alla milza. Non fu eseguita nessuna altra terapia. Il ragazzo è deceduto a casa, 40 giorni dopo l esecuzione della TC. Discussione Il carcinoma renale è una neoplasia dell età adulta con un picco di incidenza intorno alla sesta decade di vita. Nei bambini e negli adolescenti è raro, rappresentando meno del 7% dei tumori maligni primitivi del rene 3 (e meno del 4% dei tumori renali primitivi); in questa fascia d età gli istotipi più frequenti sono la variante a cellule chiare 4 e il carcinoma a cellule cromofobe 5. I carcinomi renali dell età pediatrica differiscono da quelli che insorgono in età adulta in quanto spesso si associano a specifiche anomalie cromosomiche. Tra queste, le più comuni sono le traslocazioni che interessano il cromosoma Xp11.2 e comportano una fusione del gene TFE3; infatti nella classificazione WHO è stata inserita una variante di carcinoma renale, definita appunto carcinoma renale con traslocazione Xp11.2/fusione del gene TFE3, caratterizzata da un diverso comportamento clinico e da una predilezione per l età pediatrica e giovane adulta. Un altra anomalia ben nota è quella che interessa la regione genica VHL localizzata nel cromosoma 3p25-26 che si riscontra nei carcinomi renali a cellule chiare associati alla sindrome von Hippel-Lindau, che insorgono in pazienti più giovani rispetto ai carcinomi usuali. In una serie di carcinomi renali dell età pediatrica riportata 7 sono state descritte infatti una perdita della eterozigosi della regione genica VHL e un instabilità dei microsatelliti. I carcinomi renali dell età pediatrica differiscono, inoltre, da quelli dell età adulta anche per alcuni aspetti morfologici, essendo più frequenti i sottotipi ad architettura papillare 8 e le varianti inusuali, quali il carcinoma a cellule chiare associato a tumore di Wilms 7 e casi di carcinoma renale associati a neuroblastoma, insorto dopo trattamento chemioterapico 9. Il carcinoma dei dotti collettori di Bellini è una rara variante di carcinoma renale con distinti aspetti clinici e istopatologici 10 che insorge in età più giovane rispetto al carcinoma renale convenzionale 11, presenta una predominanza maschile e si riscontra in pazienti con familiarità per patologia neoplastica 12. È una neoplasia inusuale e ancora più raro è il suo riscontro nei bambini e negli adolescenti; in letteratura ne sono riportati circa otto casi (Tab. II) Insorge tipicamente nella midollare del rene, dai dotti collettori distali, anche se sono descritti casi insorti nella corticale 15. Macroscopicamente ha margini mal definiti, spesso infiltrativi con frequente estensione al tessuto adiposo del seno renale e perirenale. Microscopicamente presenta vari pattern di crescita, più frequentemente tubulare o tubulo-papillare, talora microcistico, che conferisce alla neoplasia un aspetto spugnoso, e/o solido con possibile componente a cellule fusate di aspetto sarcomatoide È tipico il riscontro di una marcata reazione desmoplastica dello stroma circostante. Occasionale è la presenza di mucina intraluminale, interstiziale o intracitoplasmatica, talora con aspetto a cellule ad anello con castone, che può simulare un adenocarcinoma mucinoso. Inusuale è il riscontro di inclusioni filamentose che simulano un tumore rabdoide 13.
5 304 A. Gurrera et al. Tab. II. Carcinoma dei dotti collettori in età pediatrica: dati clinico-patologici. Autore N. casi Sesso Età Dimensione tumore Trattamento Stadiazione Follow-up Lack 1 F 16 anni 3 cm nefrectomia, radioterapia, actinomicina D e vincristina IV (AJCC) Mts * linf ** mediastinici e para-aortici deceduto dopo 2 anni; mts * polmonari, epatiche, linfonodali Weeks 1 M 3 anni > 5 < 19 cm (range) nefrectomia?? Dimopoulos?? anni (range) > 2,7 < 14 cm (range) nefrectomia? 4-65 mesi Craver 1 M 8 anni 7 cm nefrectomia interferon-α mts * pleurica, polmonare, linf ** retroperitoneali e diaframmatci deceduto dopo 5 gg Renshaw 2? 11 anni 2,9 cm nefrectomia T1-2, N1 (AJCC) 1 paziente deceduto dopo 2 anni; 16 anni 5 cm 1 paziente no evidenza di malattia dopo 18 anni Bruder 2? 17 anni 6 cm nefrectomia?? 19 anni 5,5 cm Gurrera 1 M 11 anni 6,3 cm nefrectomia e interleuchina * mts: metastasi; ** linf: linfonodi pt3 N2 (TNM) deceduto dopo 40 gg; mts * linf **, epatiche, polmonari e addominali Sebbene la maggior parte dei carcinomi dei dotti collettori riportati in letteratura insorga come neoplasia renale isolata, occasionalmente sono stati descritti casi in associazione con carcinomi renali papillari 18 ed oncocitomi 19. Nel caso da noi descritto la neoplasia presentava la tipica localizzazione midollare e l origine della neoplasia dai dotti collettori era supportata dal riscontro di aspetti displastici nei dotti viciniori e dalla positività immunoistochimica per citocheratine 7, 8, 18, per citocheratine ad alto peso (34βE12) e per l antigene epiteliale di membrana (EMA), a conferma dell origine dalle cellule del tubulo distale che normalmente esprimono questi antigeni 12 ; la vimentina e la racemasi antigeni espressi insieme alle citocheratine a basso peso dai carcinomi renali convenzionali che originano dalle cellule dei tubuli prossimali risultavano invece negative. La diagnosi differenziale veniva posta con il carcinoma renale di tipo midollare. Questa neoplasia, pur insorgendo dai dotti collettori distali, è considerata un entità distinta di carcinoma renale. Essa tipicamente insorge in soggetti giovani (range anni) e si associa quasi sempre ad anemia falciforme 21. Istologicamente è caratterizzata da un prevalente pattern di crescita di tipo reticolare, che ricorda il tumore del sacco vitellino, associato ad un pattern di crescita tubulare/adenoido-cistico. Lo stroma è marcatamente desmoplastico, come nel carcinoma dei dotti collettori. Tuttavia, nel nostro caso, l assenza di emoglobinopatie e, istologicamente, del tipico pattern reticolare e tubulare/adenoido-cistico, ci consentiva di escludere il carcinoma renale di tipo midollare. Il carcinoma dei dotti collettori che insorge in età adulta non sembra essere associato a specifiche anomalie cromosomiche, anche se è stata riportata una monosomia per i cromosomi 1, 6, 14, 15 e Queste anomalie non sono state riscontrate invece nei carcinomi dei dotti collettori dell età pediatrica, i quali sembrano essere correlati invece ad una elevata instabilità dei microsatelliti (MSI) 7, suggerendo che questo fenomeno possa avere un importante ruolo patogenetico. Conclusioni Il caso da noi descritto conferma che il carcinoma dei dotti collettori dell età pediatrica, così come quello insorto in età adulta 23, è caratterizzato da un decorso clinico aggressivo e da una prognosi infausta. Il trattamento è limitato
6 Carcinoma dei dotti collettori di Bellini in età pediatrica 305 alla sola resezione chirurgica, essendo la neoplasia poco sensibile sia alla chemioterapia che alla radioterapia. La maggior parte dei casi descritti si presentano con metastasi polmonari al momento della diagnosi 12 ; nel nostro caso, all esordio la malattia si presentava ad uno stadio avanzato (pt3n2) ed erano già presenti metastasi diffuse, epatiche e polmonari. Le Linee Guida del Gruppo TREP dell AIEOP prevedono in caso di nefrectomia e metastasi linfonodali un trattamento con interleuchina. Nel nostro caso, la terapia con interleuchina non riusciva a contrastare la malattia che, progredendo ulteriormente, portava rapidamente a morte il paziente. Bibliografia 1 Srigley JR, Moch H. Carcinoma of the collecting ducts of Bellini. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics. Tumours of the urinary system and male genital organs. Lyon: IARC 2004, p Murphy WM, Grignon DJ, Perlman EJ. AFIP Atlas of Tumor Pathology Series 4. Tumours of the Kidney, Bladder, and Related Urinary Structures (Kidney tumors in adults). Washington: American Registry of Pathology Lack E, Cassady JR, Sallan SE. Renal cell carcinoma in childhood and adolescence: a clinical and pathological study of 17 cases. J Urol 2006;133: Cook A, Lorenzo AJ, Salle JL, Bakhshi M, Cartwright LM, Bagi D, et al. Pediatric renal cell carcinoma: single institution 25-year case series and initial experience with partial nephrectomy. J Urol 2006;175: Campus R, Nozza P, Dell acqua A, Sementa AR, Gambini C, Dodero P. Eosinophilic chromophobe renal cell carcinoma in child with hypospadias. Pediatr Blodd Cancer 2006;11. 6 Argani P, Ladanyi M. Renal carcinoma associated with Xp11.2 translocations/tfe3 gene fusions. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics. Tumours of the urinary system and male genital organs. Lyon: IARC 2004, p Bruder E, Passera O, Harms D, Leuschner I, Ladanyi M, Argani P, et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adult. Am J Surg Pathol 2004;28: Renshaw AA, Granter SR, Fletcher JA, Kozakewich HP, Corless CL, Perez-Atayde AR. Renal cell carcinoma in children and young adult. Increased incidence of papillary architecture and unique subtype. Am J Surg Pathol 1999;23: Medeiros LJ, Palmedo G, Krigmann HR. Oncocitoid renal cell carcinoma after neuroblastoma. A report of four cases of a distint clinico-pathologic entity. Am J Surg Pathol 1999;23: Chao D, Zisman A, Pantuck AJ, Gitlitz BJ, Freedland SJ, Said JW, et al. Collecting duct renal cell carcinoma: clinical study of a rare tumor. J Urol 2002;167: Tokuda N, Naito S, Matsuzaki O, Nagashima Y, Ozono S, Igarashi T, Japanese Society of Renal Cancer. Collecting duct (Bellini duct) renal cell carcinoma: a nationwide survey in Japan. J Urol 2006;176: Craver RD, Correa H, Crapanzano JP, Kumar SR, Gardner RV. Renal collecting duct carcinoma in an 8-year-old child. Pediatr Nephrol 1996;10: Weeks DA, Beckwith JB, Mierau GW, Zuppan CW. Renal Neoplasm mimicking rhabdoid tumor of kidney. A report from the national Wilm s tumor study pathology center. Am J Surg Pathol 1991;15: Dimopoulos MA, Logothetis CJ, Markowitz A. Collecting duct carcinoma of the kidney. Br J Urol 1993;71: Gurocak S, Sozen S, Akyurek N, Uluoglu O, Alkibay T. Cortically located collecting duct carcinoma. Urology 2005;65: Gong Y, Sun X, Haines GK 3rd, Pins MR. Renal cell carcinoma, chromophobe type, with collecting duct carcinoma and sarcomatoid components. Arch Pathol Lab Med 2003;127: Aita K, Tanimoto A, Fujimoto Y, Monomura S, Takemoto F, Hara S, et al. Sarcomatoid collecting duct carcinoma arising in the hemodialysis-associated acquired cystic kidney: an autopsy report. Pathol Int 2003;53: Matei DV, Rocco B, Varela R, Verweij F, Scardino E, Renne G, et al. Synchronous collecting duct carcinoma and papillary renal cell carcinoma: a case report and review of the literature. Anticancer Res 2005;25: Yousef GM, Ejeckam GC, Best LM, Diamandis EP. Collecting duct carcinoma associated with oncocytoma. Int Braz Urol 2005;31: Fleming S, Lewi HJ. Collecting duct carcinoma of the kidney. Histopathology 1986;10: Davis CJ. Renal medullary carcinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics. Tumours of the urinary system and male genital organs. Lyon: IARC 2004, p Fuzesi L, Cober M, Mittermayer C. Collecting duct carcinoma: cytogenetic characterization. Histopathology 1992;21: Rodriguez A, Patard JJ, Lobel B. Renal cell carcinoma in young adults: incidence, disease outcome and review of the literature. Arch Esp Urol 2002;55:
7 pathologica 2007;99: Caso clinico Granuloma faciale Granuloma facciale A. KHALED, M. JONES, R. ZERMANI *, B. FAZAA, K. BACCOUCHE **, S. BEN JILANI *, M.R. KAMOUN Department of Dermatology Charles Nicolle Hospital of Tunis; * Department of Anatomopathology Charles Nicolle Hospital of Tunis; ** Dermatologist, Nabeul Key words Granuloma faciale Parole chiave Granuloma facciale Summary Granuloma faciale is a rare, benign skin condition that usually occurs on the face. Using an exemplary case of granuloma faciale, we will present the clinical and histological characteristics of this dermatosis. A 49-year-old man presented with a 6-month history of a 10 mmdiameter asymptomatic papulo-nodular red-brown lesion of the nose. A biopsy specimen led to the diagnosis of granuloma faciale. The patient received a session of pulsed-dye laser therapy, which led to significant improvement. This benign and usually isolated dermatosis can more rarely be extrafacial. It may often be mistaken for other benign dermatoses (sarcoidosis, discoid lupus erythematosus) as well as for malignant dermatoses (lymphoma, basal cell carcinoma). Histology is key to correct diagnosis. Riassunto Il Granuloma facciale è uno stato benigno raro della pelle che si presenta solitamente sulla faccia. Attraverso un caso isolato del granuloma facciale, preciseremo le particolarità cliniche ed istologiche di questa dermatosi: un uomo di 49 anni si è presentato con una lesione di 6 mesi marrone-rosso papulo-nodulare asintomatica del naso di 10 millimetri di diametro. È stata effettuata una biopsia della lesione che ha condotto alla diagnosi del granuloma facciale. Il nostro paziente ha ricevuto un applicazione di laser pulsed-dye con un notevole miglioramento. Questa dermatosi, benigna e solitamente solitaria, può raramente essere extrafacciale. Può essere confusa spesso con altre dermatosi benigne (sarcoidosi, erythematosus discoid lupus) e perfino dermatosi maligne (linfoma, carcinoma basocellulare). Ecco perché l istologia è la chiave per una diagnosi corretta. Introduction Granuloma faciale is a rare, benign condition of the skin that usually occurs on the face, although extra-facial forms have been described. The lesion can be mistaken for other benign or malignant dermatoses. Histopathology is thus key to correct diagnosis. Herein the authors present an isolated case of granuloma faciale, and present the clinical and histological characteristics and treatment options for this dermatosis. Fig. 1. Erythematous papulo-nodular lesion of the nose with dilated ostia of infundibula on the surface. Case report A 49-year-old man presented with a 6-month history of an asymptomatic papulo-nodular lesion of the nose. Upon examination a 10 mm-diameter red-brown nodule marked on its surface by patulous ostia of infundibula Correspondence Dr Khaled Aida, Résidence Diar Ezzahra 4 immeuble Ambar Appartement 94, 2034 Ezzahra Tunisia - Tel Fax
8 Granuloma faciale 307 was visible (Fig. 1). There were no laboratory findings. A biopsy specimen showed a dense mixed-inflammatory-cell infiltrate of the dermis (Fig. 2) composed of lymphocytes, plasma cells, macrophages, eosinophils and neutrophils, which were sometimes leukocytoclastic and infiltrate was concentrated around ectatic blood vessels (Fig. 3) that house fibrin in their wall; extrava- Fig. 4. Spared papillary dermis or Grenz zone. Fig. 2. Dense inflammatory dermic infiltrate. sated erythrocytes could also be observed. The lesion spared the overlying epidermis and the papillary dermis forming a Grenz zone (Fig. 4). These findings lead to the diagnosis of granuloma faciale. The patient received a session of pulsed-dye laser with subsequent improvement of the lesion. Discussion Fig. 3. Infiltrate concentrated around ectatic blood vessels composed of lymphocytes, plasma cells, macrophages, eosinophils and neutrophils sometimes leukocytoclastic with extravasated erythrocytes and perivascular fibrin deposits. Granuloma faciale is a rare benign granulomatous condition of unknown aetiology that affects predominantly middle-aged men 1. It was first described as cutaneous eosinophilic granuloma by Lever in the 1950 s 2. The lesion, often solitary (in two-thirds of cases) 2 3, appears as red-brown or purple, rarely ulcerated, papule, nodule or plaque. It is generally asymptomatic and only rarely does it cause pruritus. Dilated ostia of infundibula on its surface are suggestive of diagnosis 3. Superficial telangiectasia can also be observed 2. Granuloma faciale is usually located on the face (95% in Ortonnes s series 2 ) where it tends to occur on the nose (27%), forehead (25%) or cheeks (21%). Extra-facial locations are rare but cases where the trunk, upper limbs or scalp are involved have been also reported 4-6. When two locations coexist, the facial lesion is generally the first to appear 7. Clinically, granuloma faciale can lead to erroneous diagnosis of cutaneous sarcoidosis, lymphoma, polymorphous light eruption, discoid lupus erythematosus or even basal cell carcinoma 1. Diagnosis is based on histopathological examination, which shows a dense and polymorphous infiltrate that spares the overlying epidermis and the papillary dermis (Grenz zone) (Fig. 4) and concentrates around ectatic blood vessels (Fig. 3). This infiltrate is composed of lymphocytes, plasma cells, macrophages, eosinophils and neutrophils that are sometimes leukocytoclastic (Fig. 3). Extravasated erythrocytes, hemosiderin deposits and fibrin peri-vascular deposits may also be observed. All these features were present in our case, although none is mandatory for diagnosis. Indeed, even those lesions considered as classic, can be absent in confirmed granuloma faciale 1.
9 308 A. KHALED et al. The infiltrate composition depends on the age of the lesions. Early plaques show a predominance of eosinophils 1 and fibrinoid necrosis 3, whereas in more mature lesions, the infiltrate is lympho-histiocytic with occasional perivascular fibrosis 3. Erythema elevatum diutinum may constitute a histological differential diagnosis of granuloma faciale, especially in extrafacial locations, since it shows vasculitis with a dense inflammatory infiltrate composed of leukocytoclastic neutrophils. Neither the biological characteristics associated with granuloma faciale, apart from a moderate and inconstant elevation in blood eosinophils, nor pathological associations have been described. These lesions are benign but persistent, growing slowly and rarely ulcerating. Treatment remains unclear because of the lack of randomised studies. Many treatments have been attempted with limited or transitory benefits (antimalarials, dapsone, topical or intralesional corticosteroids, clofazimine, PUVA therapy, liquid nitrogen, surgical excision, argon laser, CO2 laser) 5. Promising results, particularly regarding the aesthetic aspects have been reported with cryosurgery 8 and pulsed-dye laser 6 9. Our patient received the latter treatment with subsequent clinical improvement. References 1 Ortonne N, Wechsler J, Bagot M, Grosshans E, Cribier B. Granuloma faciale: a clinicopathologic study of 66 patients. J Am Acad Dermatol 2005;53: Lever WF, Lane CG, Dowling JG, Spangler AS. Eosinophilic granuloma of the skin. Report of three cases. Arch Derm Syphil 1948;58: Marcoval J, Moreno A, Peyri J. Granuloma faciale: a clinicopathological study of 11 cases. J Am Acad Dermatol 2004;51: Rutten A, Hantschke M, Schwarz B, Voll U, Kingreen V, Schaller J. Extrafacial granuloma eosinophilicum. Hautarzt 2006; Oct 19 (Epub ahead of print). 5 Radin DA, Mehregan DR. Granuloma faciale: distribution of the lesions and review of the literature. Cutis 2003;72: Inanir I, Alvur Y. Granuloma faciale with extrafacial lesions. Br J Dermatol 2001;145: Ammirati CT, Hruza GJ. Treatment of granuloma faciale with the 585-nm pulsed dye Laser. Arch Dermatol 1999;135: Panagiotopoulos A, Anyfantakis V, Rallis E, Chasapi V, Stavropoulos P, Boubouka C, et al. Assessment of the efficacy of cryosurgery in the treatment of granuloma faciale. Br J Dermatol 2006;154: Cheung ST, Lanigan SW. Granuloma faciale treated with the pulsed-dye laser: a case series. Clin Exp Dermatol 2005;30:373-5.
10 pathologica 2007;99: Caso clinico Intraventricular neurocytoma: case report Neurocitoma intraventricolare: caso clinico S. Ulivieri, G. Oliveri Department of Neurosurgery, Santa Maria alle Scotte Hospital, Siena, Italy Key words Central neurocytoma Intrventricular neoplasm Magnetic resonance imaging Parole chiave Neurocitoma Tumore ventricolare Risonanza magnetica nucleare Summary Intraventricular neurocytoma is a rare, usually benign tumour of neuronal differentiation, recently recognized as a clinico-pathological entity in comparison to the other intraventricular tumours. It is generally found in the lateral or third ventricles in close relationship with the septum pellucidum, and commonly affects young adults. The authors present a case of an intraventricular neurocytoma in a 25-year-old male and discuss the importance of diagnostic criteria, pathological findings and management of these tumours. Riassunto Il neurocitoma intraventricolare è un tumore raro, frequente nei pazienti giovani, recentemente riconosciuto come un entità clinico-patologica nuova rispetto agli altri tumori de ventricoli cerebrali, generalmente localizzato nel terzo o nei venticolo laterale e spesso a contatto con il setto pellucido. Viene presentato il caso clinico e la letteratura attinente revisionata e discussa. Introduction Since the initial description of central neurocytoma by Hassoun et al. 1, a number of reports have documented the histological, immunohistochemical and ultra structural features and clinical outcome of this neoplasm. Usually found in an intraventricular location, these tumours show clear cells intersected by a vascular meshwork. Tumours with these histological features have also been reported in an extra ventricular location, in the corpus callosum, in basal ganglia and within the parenchymal and spinal cord. More recently, a multifocal neurocytic tumour with leptomeningeal dissemination has been reported 2. Although generally associated with favourable prognosis, cases with aggressive courses have also been reported 3. Intraventricular tumours usually present with signs of occlusive hydrocephalus such as headache, nausea and visual or mental disturbances 4 5. Differential diagnosis of these tumours includes choroid plexus papilloma, ependymona, subependymal giant-cell astrocytoma, intraventricular meningioma, astrocytoma and oligodendroglioma; immunocytochemical analysis and molecular techniques can confirm the neuronal origin of the tumour. Case report A 25-year-old male presented with a history of headache lasting a few months. Neurological and physical examination was normal. CT scan disclosed a large isodense ventricular tumour entirely occupying the frontal horn of the left lateral ventricle displacing the septum to the right that was enhanced slightly after contrast injection. MRI of the brain confirmed similar features with the tumour obstructing of the foramen of Monro and the involvement of the rostrum of corpus callosum (Fig. 1). The patient underwent a left frontal craniotomy; and the left lateral ventricle was entered through a transcallosal approach. The tumour was soft and could be removed with gentle suction; the wall of the lesion was gently peeled off from the wall of the ventricle, and appeared to arise just posterior to the septum pellucidum. Histological examination demonstrated a homogenous Correspondence Dr. Simone Ulivieri, Unità Operativa Complessa di Neurochirurgia, Policlinico Santa Maria alle Scotte, Siena, Italy - Tel
11 310 S. Ulivieri, G. oliveri Fig. 1. Axial T1-weighted MRI scan shows the tumour, isointense with the cerebral cortex in the left lateral ventricle. Fig. 3. The case was synaptophysin immunopositive (Syn x 200). astrocytes within the tumour tissue, although the neoplastic cells stained negative for GFAP. The postoperative period was uneventful, with a transient neuropsychological dysfunction corresponding to frontal signs and callosal disconnection signs; there was no residual tumour detected in the postoperative CT scan, and the patient was discharged after 10 days. Discussion Fig. 2. Histomorphology of central neurocytoma (CN) showing sheets of uniform, small-to-medium-sized cells (x 100). proliferation of uniform small cells separated by zone of fine fibrillarity (Fig. 2). Honeycomb architecture, Homer-Wright rosettes and pseudo rosettes were not found. Immunohistochemistry for synaptaphysin showed a dot-like strong positivity between cells and a slightly greater positivity in the peripheral cytoplasm on neoplastic cells (Fig. 3). Glial fibrillary acid protein (GFAP) was immunoreactive for rare reactive Central neurocytoma is defined by the World Health Organization (WHO) classification of tumours as a neoplasm composed of uniform round cells with neuronal differentiation, typically located in the lateral ventricles around the foramen of Monro 6. Intraventricular neurocytoma generally have a favourable prognosis and are included in the group of WHO grade II tumours. It occurs predominantly in young adults or adolescents with an incidence of % of all intracranial tumours; both sexes are equally affected 7 8. Computed tomography (CT) scans demonstrate an iso-or slightly hyper-dense mass within the body of the lateral ventricles near the foramen of Monro; areas of hypodensity represent cystic degeneration and approximately 50% of central neurocytoma demonstrate calcification on CT imaging. Contrast enhancement is mild to moderate. Magnetic resonance imaging (MRI) usually reveals a mass that is isointense on T1 weighted imaging and on T2 is relatively isointense with the cortex. There is a moderate enhancement after administration of gadolinium 9. Central neurocytoma is composed of uniform, smallto-medium-sized cells with rounded nuclei, finely stippled chromatin (salt and pepper chromatin) and inconspicuous nucleoli, together with scant cytoplasm. The cells are either scattered diffusely or arranged in groups, separated by non-branching, thin-walled vascular channels; in certain areas they
12 Intraventricular neurocytoma 311 are arranged in a fibrillary background. However the presence of small areas of necrosis, nuclear plemorphism and increased mitotic activity are features of malignancy. Vascularity is represented by long, thinwalled capillary-sized vessels, which are arranged in a linear arborizing pattern, give rise to an endocrine appearance. In many cases, thin walled dilated vascular channels, and foci of calcification are readily identified. In places, tumours display dense cellular areas alternating with fibrillary/ acellular areas. The latter components are mainly perivascular and have a fine fibrillary neuropil matrix mimicking rosettes of ependymoma. Immunostaining for neuron-specific enolase (NSE) and synaptophysin confirm the neuronal nature of the neoplasm. Typically, synaptophysin immunoreactivity is noted in the neuropil, especially in fibrillary zones and perivascular cell-free areas, and not in the cell bodies of normal neurons. False cytoplasmic immunopositivity may be attributed to preexistent neuropil or neuronal structures, or faulty antigen retrieval techniques and/or use of polyclonal antisynaptophysin antibodies. However, false immunonegativity ascribed to spontaneous absence of immunoreactivity, small biopsies or technical difficulties does not rule out a diagnosis of neurocytoma. Glial fibrillary acid protein (GFAP) staining can be found in central neurocytomas. It is unclear whether these cells represent neoplastic or reactive astrocytes; it has been suggested that central neurocytomas originate from bipotential (neuronal and astrocytic) progenitor cells in the periventricular region that persist into adulthood 10. Electron microscopy demonstrates clear and dense core vesicles, microtubules and synapse formation. Molecular analysis for the detection of chromosomal anomalies in intraventricular neurocytomas can be performed with a number of tests, and genomic alterations have been found in 60% of cases 11. Most neurocytomas are cytologically and mitotically unremarkable. Cytogenetic and molecular studies for neurocytomas have yielded variable and inconsistent results, but have included loss of chromosome 17 12, gain of chromosomes 2p, 10q, 18q 13, and isochromosome Owing to their artifactual cytoplasmic vacuolations and monomorphic histologic appearances, neurocytomas, and especially extraventricular neurocytoma, must be differentiated from oligodendroglial tumors. An intraventricular tumour with a solid, noninfiltrating pattern along with perivascular pseudorosettes warrants differential diagnosis with ependymomas. Other differential diagnoses of neurocytomas include astrocytomas, mixed gliomas, neuroblastomas, hemangioblastomas and, more rarely, metastases. Central neurocytomas are thought to represent the benign end of the spectrum of neuronal tumors that are generally amenable to surgical excision, with an overall favorable outcome. The surgical approaches for these lateral ventricular tumours include the transcallosal or transventricular routes 15. The hydrocephalus should be treated only if it persists after surgery. An important aspect of clinical management concerns the sensitivity of these lesions to radiation therapy. The histopathological features of prototype neurocytomas, such as advanced neuronal differentiation, low mitotic activity, absence of vascular endothelial proliferations and tumour necrosis suggest a relative resistance to ionizing radiation. The experience with chemotherapy for central neurocytoma has been more limited. In the series of Schild et al. 16, four patients received chemotherapy after radiation and there was no tumour progression by CT and MRI imaging. Various combinations of carmustine, lomustine, prednisone, vincristine and cisplatin have been used. We propose complete microsurgical removal of the tumour as the treatment of choice for intraventricular neurocytoma; radiotherapy eventually followed with chemotherapy should be reserved for specific cases, such as subtotal resection and in malignant or recurrent tumours. References 1 Hassoun J, Gambarelli D, Grisoli F, Pellet W, Salamon G, Pellisier JF, et al. Central neurocytoma: an electronmicroscopic study of two cases. Acta Neuropathol 1982;56: Yamamoto T, Komori T, Shibata N, Toyoda C, Kobayashi. Multifocal neurocytoma with extensive leptomeningeal dissemination in the brain and spinal cord. Am J Surg Pathol 1996; 20: Sharma MC, Sarkar C, Kaaraak AK, Gaikwad S. Intraventricular neurocytoma: a clinicopathological study of 20 cases with review of the literature. J Clin Neurosc 1999;6: Dodero F, Alliez JR, Metellus P, Hassan H, Hassoun J, Alliez B. Central neuorcytoma: 2 case reports and review of the literature. Acta Neurochir 2000;142: Patil AA, McComb RD, Gelber B, McConnell J, Sasse BS. Intraventricular neurocytoma: a report of two cases. Neurosurgery 1990;26: Hwei YL, Khoon LG, Lai PG. An intraventricular tumour in a young woman. Pathology 2002;34: Drevelengaas A, Polyzoides K, Kaalaaitzoglou I. Intraventricular neurocytoma; case report and review. Eur J Radiol 1994;19: Tacconi L, Thom M, Symon L. Central neurocytoma: a clinicopathological study of five cases. Br J Neurosurg 1997;11: Zhang D, Wen L, Henning TD, Feng XY, Zhang YL, Zou LG, et al. Central neurocytoma: clinical, pathological and neuroradiological findings. Clin Radiol 2006;61: Jay V. Central neurocytoma: morphological. Flow cytometric, polymerase chain reaction, fluorescence in situ hybridization and karyotypic analyses. J Neurosurg 1999;90: Schmidt MC, Gottfried ON, Von Koch CS, Chanag SM, McDermott W. Central neurocytoma: a review. J Neurooncol 2004;66: Cerda-Nicholas M, Lopez-Gines C, Peydro-Olaya A, Llombart- Bosch A. Central neurocytoma: a cytogenetic case study. Cancer Genetics Cytogenet 1993;65: Jay V, Edwards V, Hoving E, Rutka J, Becker L, Zielenska M, Teshima I. Central neurocytoma: morphological, flow cytometric, polymerase chain reaction, fluorescent in situ hybridization, and karyotypic analyses. Case report. J Neurosurg 1999;90:
13 312 S. Ulivieri, G. oliveri 14 Yin XL, Pang JC, Hui AB, Ng HK. Detection of chromosomal imbalances in central neurocytomas by using comparative genomic hybridization. J Neurosurg 2000;93: Yasargil MG, Von Ammon K, Von Deimling A, Valavanis A, Wichmann W, Wiestler OD. Central neurocytoma: histopathological variants and therapeutic approaches. J Neurosurg 1992;76: Schild SE, Scheithauer BW, Haddock MG. Central neurocytomas. Cancer 1997;79:790-5.
15 Program 22 nd of June pm: Registration pm: Welcome ceremony Vladimiro Mambelli, President of the Congress Paolo Spinucci, President Pio Sodalizio dei Piceni Andrea Segré, Representative Uniadrion Michele Carmosino, General Manager Asur 13 - Ascoli Piceno pm: Keynote Lecture J. Rosai Department of Pathology Centro Diagnostico Italiano Diseases and deaths in the Medici s of Florence pm: Concert (Teatro Regio, Parma) 23 rd of June 8.30 am Soft tissue tumours Chairpersons: Oscar Nappi, Bettina Zelger Juan Rosai (Milano, Italy) Typing vs. grading in soft tissue tumours Thomas Mentzel (Friedrichshafen, Germany) Sarcomas of the skin am Coffee break am Proffered papers Chairmen: Lucio Palombini, Bozo Kruslin Louis Rosati (Tempe, Arizona USA) Influenza: past, present and the potential pandemic pm Lunch pm Familial cancer & susceptibility to cancer Chairpersons: Riccardo Cellerino, Angelika Reiner Fatima Carneiro (Porto, Portugal) Pathology and genetics of gastric cancer Gianni Romeo (Bologna, Italy) Mitochondria and thyroid cancer pm Coffee break pm Proffered papers Chairpersons: Michele De Nictolis, Sezana Grazio pm Friendly session Chairmen: Giuseppe Viale, Vincenzo Eusebi Riccardo Masetti (Roma, Italy) Komen Italia and breast cancer Agostino Faravelli (Milano, Italy) Intarsio e patologia (Inlay and pathology) pm Business meeting pm Social dinner 24 th of June 9.00 am Technology applied to pathology Chairpersons: Franco Fedeli, Nina Gale Manfred Dietel (Berlin, Germany) Predictive pathology. A challenge in clinical diagnostic and pharmaceutical drug development Fabio Facchetti (Brescia, Italy) New techniques in hematopathology A.P. Beltrami (Udine, Italy) Cancer stem cells Coffee break Proffered papers Chairpersons: Gianni Massarelli, Majda Vucic Borse di Studio (Prize) ceremony Scientific Committee: Vladimiro Mambelli (Ascoli Piceno), President of the Congress and Elect President of the Adriatic Society of Pathology; Carlo Alberto Beltrami (Udine), Gianni Bussolati (Torino), Vincenzo Eusebi (Bologna), Guidalberto Fabris (Ancona), Sezana Gratio (Ljubljana), Sigurd Lax (Graz), Lucio Palombini (Napoli), Valdi Pisac-Presutic (Split), Giorgio Stanta (Trieste) Committee for the Pio Sodalizio dei Piceni (Borse di Studio) Prizes: Paolo Spinucci (Roma), President; Vladimiro Mambelli (Ascoli Piceno); Gregor Mikuz (Innsbruck); Juan Rosai (Milano); Sven Seiwert (Zagreb); Duilio Benvenuti (Roma); Giorgio Bizzarri (Roma) Organizing secretariat: Dr.ssa Marina Del Vecchio Servizio di Anatomia Patologica Ascoli Piceno
16 pathologica 2007;99: Concurrent histopathologic diagnoses in endometrioid endometrial carcinoma C. Amalinei, R. Balan, I. Draga Caruntu, S. Butureanu *, M. Pavaleanu ** Department of Normal and Pathological Morphology, University of Medicine and Pharmacy Gr.T. Popa Iasi, Romania; * Department of Obstetrics and Gynecology, University of Medicine and Pharmacy Gr.T. Popa Iasi, Romania; ** III Obstetrics and Gynecology Clinic, Iasi, Romania Clinicopathologic, immunohistochemical, and molecular genetic studies have provided data for a dualistic model of endometrial carcinogenesis. Type I or endometrioid subtype, the most common form, is associated with unopposed estrogenic stimulation, as well as the presence of endometrial hyperplasia as precursor, frequently diagnosed as concurrent lesions on biopsies or on surgical specimens. Simultaneous cancers involving the endometrium and ovary are well recognized, the identification of the primary neoplasm orientating prognosis and treatment. Another coexistent location is the cervix and the correct diagnosis requires exclusion of cervical invasion by the endometrial carcinoma. The aim of our study was to investigate histopathological and immunohistochemical particularities of these categories of coexistent lesions, selecting from our files 42 cases of endometrial endometrioid carcinomas (EECs), 22 cases with concurrent endometrial hyperplasias, 13 cases of synchronous ovarian carcinomas, and 7 cases of synchronous cervical carcinomas, using adjuvant histochemical and immunohistochemical stainings, in selected cases. Endometrial hyperplasias, architecturally classified into simple and complex, and cytological without atypia and atypical type, corresponded to recent criteria of endometrial intraepithelial neoplasia (EIN), and were characterized by high expression of estrogen receptors (ERs), of Ki-67 and Cyclin D1. Synchronous ovarian and EECs were diagnosed in 3 cases, as mucinous pattern was noted in ovarian counterpart. Corroborating clinical, histological and immunohistochemical findings, 8 synchronous ovarian tumors were primary endometrial and metastatic ovarian, and one primary ovarian, probably developed on an endometriotic focus, and secondary endometrial, exhibiting an endometrioid pattern. Coexistent cervical carcinomas were diagnosed in 3 cases, exhibiting different histologic features: adenosquamous pattern in 5 cases and squamous type in 2 cases. Interestingly, 2 of the investigated cases belonged to multiple cancer syndromes: one associating concomitant endometrial and ovarian carcinomas, and a metachronous retroperitoneal malignant peripheral nerve sheath tumor (MPNST) and another diagnosed with concomitant endometrial, ovarian, and cervical carcinomas followed by a metachronous breast carcinoma. Conclusions. Investigated cases reflect different steps along the pathways of feminine genital tract carcinogenesis, especially particular in EECs, revealing their origin in EIN, their propensity to adnexal and/or cervical extension or to multiple primaries, along the genital tract, as an illustrative feature for cancerization field effect. Furthermore, some cases may represent the first manifestation of a multiple cancer syndrome, so a careful examination and follow-up is required in patients diagnosed with endometrial carcinomas. Myxoid modification in well-differentiated and dedifferentiated liposarcoma A. Ambrosini-Spaltro, A. Farnedi, G. Tallini Department of Anatomic Pathology, University of Bologna at Bellaria Hospital, Bologna, Italy Introduction. Myxoid liposarcoma is one of the most common subtype of liposarcomas. Myxoid differentiation can be focally observed also in liposarcoma subtypes that do not belong to the myxoid group. The aim of the present study is to analyze myxoid modification in well-differentiated and dedifferentiated liposarcomas. Materials and methods. Fifty-six cases of well-differentiated and dedifferentiated liposarcomas were retrieved from the archives of the Department of Anatomic Pathology at Bellaria Hospital in Bologna. All the slides were reviewed and the following morphologic parameters were assessed: myxoid stromal change, extent and features of the capillary network, presence and number of lipoblasts and of multinucleated cells, steatonecrosis, and cellular atypia. We also studied the presence and the distribution of non lipogenic components within the tumor: sclerosing areas, areas of low grade dedifferentiation and areas of high grade dedifferentiation. Five samples from 3 cases were successfully karyotyped. Results. Tumors included 49 well-differentiated liposarcomas (44 lipoma-like, 5 sclerosing), 4 liposarcomas with high grade dedifferentiation, 3 mixed liposarcomas (1 case of myxoid/ well-differentiated liposarcoma, 2 cases of myxoid/well-differentiated liposarcoma with high grade dedifferentiation). Recurrences were observed in 4 cases: 2 well-differentiated sclerosing liposarcomas and 2 high grade dedifferentiated liposarcomas. Myxoid stromal change was identified in 12 cases; in 8 of the 12 cases there were also areas with thinwalled capillary vessels organised to reproduce a chickenwire network indistinguishable form that observed in classic myxoid liposarcoma. Myxoid stromal change with an irregular network of thick-walled vessels was identified in 6 cases. Areas containing only myxoid matrix without any defined capillary network were present in 3 cases. Lipoblasts were detected in 49 cases, atypical multinucleated cells in 20 cases, foci of steatonecrosis in 27 cases, significant cellular atypia in 8 cases, including all liposarcomas with high grade dedifferentiated areas. Non lipogenic components were present in 31 cases: sclerosing areas were observed in 29 cases, areas of low grade dedifferentiation in 11 cases, areas of high grade dedifferentiation in 6 cases. The non lipogenic (sclerosing or dedifferentiated) component of the tumor was sharply separated in 7 of the 30 cases. Cytogenetic analysis revealed non clonal alterations including 1p-, -15, -22 in 1 case (well-differentiated liposarcoma), a ring chromosome in 1 case (mixed liposarcoma) and a giant chromosome in 1 case (well-differentiated liposarcoma). Conclusions. Well-differentiated liposarcomas exhibit an extremely variable morphologic appearance with myxoid modification, non lipogenic areas and dedifferentiated components. Myxoid change, including areas with a thin-walled capillary network indistinguishable from that observed in classic myxoid liposarcoma, is not uncommon in well-differentiated and dedifferentiated liposarcomas; it may represent a pitfall in the differential diagnosis with myxoid liposarcoma. Since rings and giant marker chromosomes are the hallmark of well-differentiated and dedifferentiated liposarcomas, their identification by cytogenetic analysis is useful for tumor typing.
17 316 Adriatic Society of Pathology - 22 nd International Meeting Histological sectioning of brush bristles allows improved diagnosis of biliary tract S. Asioli, G. Accinelli, E. Armando, D. Pacchioni, P. Cassoni, G. Bussolati Department of Biomedical Sciences and Oncology, University of Turin, Italy Introduction. Biliary tract brush cytology is increasingly being recognized as a favoured method for evaluating abnormalities of the pancreatic and biliary tract. In order to increase the diagnostic potential of endoscopic brushing of the biliary tract, we devised a novel technique finalized to the complete and ideal cytologic examination of the collected material through an original new brush processing method. Material and methods. 112 consecutive pancreato-biliary brush cytology specimens (67M; 45F) collected at Molinette Hospital, University of Turin, between January 2002 and August 2006 were included in our study. All patients had a definite final benign or malignant diagnosis based either on independent histological or cytological sampling, or on clinical follow-up data (follow-up was median 21 months). Immediately following brushing, the brush is immersed into methanol; then, in order to induce formation of a glue surrounding the brush, in the pathological laboratory it is immersed into egg albumen (a mixture 1:1 of egg albumen and glycerol), and finally returned to methanol. For paraffin embedding, the metal handling is cut away and the remaining brush is introduced into a cassette: paraffin-embedded sections parallel to the long axis of brush are cut until the metal wire is almost reached, then the block is rotated and new sections are obtained from the opposite side. Small fragments of the mucosa, of inflammatory cell aggregates or of carcinomas (stained in Haematoxylin & Eosin and Alcyan blue mucine) were observed in our series, and displayed an optimal fixation allowing a definite diagnosis which proved mandatory for proper therapy in the almost totality of cases. Results. The results obtained on 112 consecutive cases using such technique showed a satisfactory sensibility when compared to final histological diagnosis, this method showed: 87% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 91% negative predictive value (NPV). Moreover when compared this method to the patient clinical diagnosis, after at least 6 months follow-up, it showed: 88% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 96% negative predictive value (NPV). Conclusion. Finally such novel technique proved to be highly sensitive and specific, limiting the un-satisfactory cytological diagnoses to less than 1% and providing a 88% concordance (K value) with the final histology at surgery and a 91% concordance (K value) with patient follow-up. Cutaneous rosai dorfman disease without limphadenopathy. A case report N. Bilalovic, A. Cimic, E. Lazovic, A. Cvorak * Department of Pathology, Clinical Centre University Sarajevo, Bosnia and Herzegovina; * Department of Plastic Surgery, Clinical Centre University Sarajevo, Bosnia and Herzegovina Rosai-Dorfman disease or sinus histiocytosis with massive lymphadenopathy is benign proliferation of histiocytes characterized in it s typical form as painless, bilateral lymph node enlargement of the neck or any group of lymph nodes. About 15% of patient may have only extranodal disease. Our case is 42 years old Bosnian male presented to plastic surgeon with skin lession but with no lymphadenopathy. A microscopic feature shows dermal infiltrate with dendritic cells, histiocytes and inflammatory cells. The dendritic cells show emporipolesis for neutrophils and lymphocytes Giant cells were also present. Based on morphologic appearance and immunohistochemistry we concluded that skin biopsy is the most compatible with cutaneous Rosai-Dorfman disease. Telepathology: an occasion for young pathologists F. Bono, F. Pagni Dipartimento di Scienze chirurgiche, Università di Milano- Bicocca, U.O. Anatomia Patologica, Ospedale Civile di Vimercate, Presidio di Desio Introduction. Telepathology makes possibile diagnosis cytoand histopathologic from everywhere in the world. Patologi Oltre Frontiera s project is to provide some hospital in Africa and other countries with scanner, so they can develope a therapeutic program based on diagnoses makes from Italy, awaiting local pathologists are formed. University school of Pathology can collaborate with this project establishing a network that enrich younger pathologists with a new competence and supports the health in the developing countries. Materials and methods. Till then, just one hospital (Mtendere Mission Hospital of Chirundu, Zambia) has scanner, but some other hospital will have it. Slide scannerized is load on a server and from it is possible see digital slide on every computer by internet. Every school who will agree to this project undertakes to inspect and diagnose scannerized slides. A Pathologist tutor will be supervises the diagnoses which will be sent by to the persons responsible for the project. Discussion. In this presentation we want to show the involvement project of the schools with the activity of Patologi Oltre Frontiera: an inalienable chance to acquire expertise and specializations for the young pathologists, and to awaken everybody to the diagnosis shortage in the poorest countries. Osteosarcoma study L. Brcic, D. Anzulovic, I. Ilic, V. Loncaric, I. Kosuta, J.S. Giljevic *, D. Orlic **, S. Seiwerth Institute of Pathology, Medical School University of Zagreb, Zagreb, Croatia; * Department of Oncology, Children s Hospital Zagreb, Zagreb, Croatia; ** Department of Orthopaedic Surgery, University Hospital Center Zagreb, Zagreb, Croatia A retrospective study of osteosarcoma in children and adolescents during a 20 years period (1987 till 2006) was performed. From the archives of the Institute of Pathology, Medical School and Department of Pathology, University Hospital Center Zagreb, 80 cases were retrieved. A part of diagnostic biopsies and most of surgery was performed at the Department of Orthopaedic Surgery, University Hospital Center Zagreb. The oncological treatment and follow-up for most of
18 ABSTRACTS 317 the patients (more than 2/3) was at the Children s Hospital Zagreb. Epidemiological parameters (age, sex, survival), tumor characteristics (localization, histological type, metastases), laboratory data (BSR, LDH), chemotherapy (whether or not preoperative, protocol) were accessed. A comparison of two ten years periods ( and ) was performed. Of the 80 patients 38 were male, age range was from Most of the tumors were localized in the femur and tibia. At time of diagnosis only 3 patients had confirmed metastatic disease. The vast majority of patients were treated by preoperative chemotherapy and en block resection, followed by chemotherapy. Inadequate response to preoperative chemotherapy was noted in most patients. About 1/3 of the patients developed metastatic disease during follow-up period. The goal of this study is to make the first step in the direction of a bone tumor registry. Early and late results of the surgical cure in the cases of two malignant primary cardiac tumors D. Butcovan, G. Tinica, C. Borza Iasi Cardiology Center Cardiac sarcomas are rare malignant tumors having often a late diagnosis, because they are usually asymptomatic and malignancy criteria are sometimes difficult to define, as well. The aim of the study was to characterize the clinical and histological picture of 2 malignant cardiac tumors, to assess the prognosis and to develop a tumour management strategy for cure. We described 2 cases: the first was a primary cardiac leiomyosarcoma, located in the posterior wall of the left atrium and the second was a primary cardiac undifferentiated sarcoma, located in the right ventricle. In the leiomyosarcoma case the complete excision was made as a curative procedure, while in the cardiac undifferentiated sarcoma case the partial surgical excision was made as a palliative procedure due to the tumour invasiveness feature. The histological and immunohistochemical study revealed a differentiated leiomyosarcoma in the first case, and a high-grade pleomorphic, undifferentiated sarcoma, in the second case. Whatever histological subtypes are, malignant cardiac tumors have a poor prognosis when are undifferentiated and unresecable forms. Complementary radiotherapy or chemotherapy is ineffective, and prognosis is related more to the degree of tumoral differentiation then to the operative treatment itself. On-site cytopathological evaluation of endoscopic ultrasound-guided fine needle aspiration of pancreatic neuroendocrine tumors P. Campisi, G. Accinelli, C. De Angelis *, I. Castellano, S. Asioli, D. Pacchioni, G. Bussolati Department of Biomedical Sciences and Human Oncology, University of Turin, Italy; * Department of Gastroenterology, San Giovanni Battista Hospital, University of Turin, Italy Objectives. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is increasingly used in diagnosis of pancreatic tumors. Our study aims to identify cytological characteristics of on-site evaluation helpful for recognizing pancreatic neuroendocrine tumors (NETs). Methods. Our study comprises 5 cases of pancreatic tumors with cytological features suggestive of neuroendocrine origin, obtained by EUS-FNA which diagnosis was confirmed by surgical excision. For each case we analized: cytological smears, cell block sections and immunocytochemical stains. Results. All cases show similar and peculiar cytological characteristics of on-site evaluation: smears were richly cellular with poorly cohesive small cells; they display a monotonous basophilic appearance with scanty cytoplasm and small eccentric nucleus with speckled or dusty chromatin pattern conferring a plasmocytoid appearance. Immunocytochemical stains (Chromogranin A, Synaptophysin), performed on cell-block, confirmed neuroendocrine differentiation. Conclusion. EUS-FNA is a useful method of identification of pancreatic NETs. Recognizing cytopathological features of neuroendocrine origin improves the diagnostic yield of the procedure, allowing a three-tiered approach in planning the handling of FNA specimens. Sequencing of the mitochondrial D-loop region as a tool to discriminate between synchronous or metachronous primary lung tumours and intrapulmonary metastastatic spread G. Caprara, L. Morandi, M. Boaron *, A. Cancellieri **, K. Kawamukai *, A. Pession, G. Tallini, S. Damiani Division of Anatomic Pathology University of Bologna; * Division of Thoracic Surgery AUSL di Bologna; ** Division of Anatomic Pathology AUSL di Bologna Four to 10 percent of patients with non small cell lung carcinoma (NSCLC) present with two nodules or develop a second nodule after the initial diagnosis. Tumor stage is the most important prognostic factor in lung cancer and, therefore, the differential diagnosis between synchronous or metachronous primary lung neoplasms (pt1m) and intrapulmonary metastasis of (NSCLC) (pt4 or pm1 according to their location) is crucial for patient management. The large number of mitochondrial mitochonodrial DNA (mtdna) copies present in each tumour cell and the high frequency of mtdna mutation rate in tumours suggest that sequencing of the highly polymorphic D-loop mtdna region may be useful to discriminate synchronous/metachronous primary tumours from intrapulmonary metastases 1. We studied a retrospective series of 20 patients underwent to surgery for synchronous and metachronous NSCLC. The charts from each patient were reviewed and the tumours were staged according the current WHO and classified as multiple primary or metastases according Martini and Melamed 2. Direct DNA sequencing of the mitochondrial D-loop region was performed in all samples and the genetic distance between the multiple tumours was evaluated. Our results show that in 72% of the casess the tumours were genetically unrelated and thus should be considered as independent multiple primary cancers. It is noteworthy that in this group, in up to 65 per cent of patients, the histological type was the same in all nodules analyzed (most frequently adenocarcinoma, acinar type). In the remaining 28% of cases the mtdna sequencing revealed the same mutation pattern, compatible with origin from a single neoplastic cell clone. Thus, our study indicates that the present clinicopathologic
19 318 Adriatic Society of Pathology - 22 nd International Meeting criteria (site, histological type, etc.) for staging patients with multiple nodules of NSCLC may not be fully reliable and that molecular analysis may represent a very useful tool to discriminate multiple primary tumours from intrapulmonary metastases. References 1 Morandi L, Asioli S, Cavazza A, Pession A, Damiani S. Genetic relationship among atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and adenocarcinoma of the lung. Lung Cancer 2007;56: Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70: The dental pulp fibroblasts as morphologic markers for senescence I.-D. Caruntu, C. Amalinei, S.-E. Giusca Department of Histology, Gr. T. Popa University of Medicine and Pharmacy, Iasi, Romania One of the senescence effects at the level of dental pulp is the reduction of the pulp volume, which is frequently associated with the fibrosis and sclerosis. Within the frame of these transformations, the fibroblasts decrease in number and change their sizes. The study presents a quantitative evaluation of the dental pulp fibroblasts, based on computerized morphometry, whose objective was to investigate the variations in cell areas and perimeters for different age groups. The material consisted of dental pulp fragments obtained from patients aged between 40 and 50 years (5 cases group 1), 50 and 60 years (5 cases group 2) and 60 and 70 years (5 cases group 3). In all cases, the dental pulp was healthy (without clinical signs of inflammation) at the time when pulpectomy was requested as part of a restorative tooth treatment. For routine histopathological exam, the dental pulp fragments were formalin fixed, paraffin embedded and stained with hematoxylin-eosin and light green trichrome. From each specimen we acquired digital images corresponding to significant microscopic fields. To develop the quantitative analysis in the Zeiss KS400 environment, we designed and implemented two macros, namely PULPIMG and PULPGRP, which operate at the image and group levels, respectively. For a given image, PULPIMG automatically identifies the regions occupied by fibroblasts and measures their geometric features (areas, perimeters). For a given group, PULPGRP collects the numerical data extracted by PULPIMG from all the microscopic fields considered relevant and provides a statistical analysis. The results of our computerized approach show that the mean value of the fibroblast area decreases from group 1 to group 3, whereas the correlation between perimeters and areas is preserved (the slope of the regression line has insignificant variations from a group to another). These results support the idea that the fibroblasts morphometric profile can play the role of a marker for the dental pulp (and implicitly tooth) senescence. Clinico-morphological study in twin pregnancy R. Ciurea, I.E. Plesea, N. Patrana **, S. Bala **, L. Novac *, B. Zaharia Department of Pathology; * Department of Obstetrics and Gynecology, University of Medicine and Pharmacy; ** Department of Pathology, Emergency County Universitary Hospital, Craiova, Romania Background and aims. Multiple pregnancy and especially twin pregnancy are stillrepresenting a major issue both for medical corpus and society due to the multitude of implications in medical management and economic and social impact. The authors assessed some of the significant clinical and morphological monitoring parameters of twin pregnancies recorded during a 5 years period in Department of Obstetrics and Gynecology of Craiova Emergency County Universitary Hospital. Material and methods. The studied group consisted of 197 cases of twin pregnancy. The studied material consised of data coming from pregnant women and new born files, surgical records, antepartum ultrsond results, dead new born necropsy records and foetal appendages histopathological records. Results. There was one twin pregnancy for every 97 single pregnancies, with a lower percentage (1.07%) as compared to the literature and data from western civilised countries. The incidence of twin pregnancies was high in women at their fertility peak (26-35 years), with a significant increase with the number of pregnancies and deliveries. Twin pregnancies were more frequent in women with previous twin pregnancies and in a very small percentage in primiparous ones. The mean gestational age was weeks in more than 57% of cases, for the remaining 40% being arround 37 weeks. Dichorionic diamniotic placentas were the most frequent ones. Ultrasound examination revealed a small percentage of cases in which monochorionic diamniotic pregnancies were mistaken for dichorionic diamniotic pregnancies with fused placentas. Placental villous structures of twin pregnancies showed a morphological pattern characteristic for the third trimester of pregnancy. In 4 cases of twin transfusion syndrome, the donor shows changes in the the stromal structure of the chorionic villi together with excessive loading of the chorionic vascular bed of the receptor twin. There was a 11.5% perinatal mortality with a slight predominance in the second foetus, the most frequent deaths occuring in the first 72 hours after birth due to maladjustement to the extrauterine environment. One of the main causes of death established after the necroptic examination was the intraventricular hemorrhage. Conclusions. The pathological examination was useful to the obstetrician who took into consideration two major aspects in following and delivering a twin pregnancy: solving of controversial placentation cases through histopathological examination of the twin membranes for a correct evaluation of zygotism and, establishing the causes of perinatal and especially antepartum deaths using necroptic examination.
20 ABSTRACTS 319 PKCJ expression in Gastro-Intestinal Stromal Tumors (GIST): immuno-istochemical assessment PKCJ vs. CD117 F. Corini, M. Del Vecchio, R. Taborro, P. Lorenzini, V. Mambelli Section of Anatomic Pathology, C. e G. Mazzoni Hospital, Ascoli Piceno, Italy Introduction. Gastro-intestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Most GIST contain oncogenic gain-of-function KIT mutations and feature strong expression of the constitutively activated KIT (CD117) receptor tyrosine kinase protein. Numerous studies have demonstrated that the immuno-phenotypical expression of CD117 is specific, even if not confined, to GIST. However, in a small GIST subgroup (less than 2%), c-kit expression is negative although histological findings of gastrointestinal stromal tumors are most suspicious. The existence of c-kit negative gastrointestinal stromal tumors points to the need of additional markers for making the diagnosis. Gene expression studies using DNA microarrays have revealed that GIST show a distinct and uniform gene expression profile, wich allows distinguishing of these tumors from other malignancies of mesenchimal origin. Among the transcripts identified as discriminatory in these studies, the gene encoding protein kinase C (PKCJ) was overexpressed in GIST samples. PKCJ is a serine/threonine kinase that is transcriptionally upregolated in GIST compared with other soft tissue tumors. It is selectively expressed in the interstitial cell of Cajal lineage; it s also involved in T-cell activation, in skeletal muscle signal transduction and in neuronal differentiation. The aim of this study is to confirm the importance of the analysis of CD117 expression as a specific marker of GIST and, at the same time, to assess the PKCJ expression as a new diagnostic marker of this tumors. Material and methods. Study group: 35 cases of stromal neoplasia have been selected from the central files of the Mazzoni Hospital (Ascoli Piceno), with the following localization: stomach (12), small and large intestine (15), peritoneum (3), retro-peritomeum (3), omentum (1), duodenum (1). Immuno-istochemistry: Sections of histological specimen (4 micron thick; microtome Leica DSC1) have been obtained from the tissue material, fixed in formalin and embedded in paraffin. The monoclonal antibody PKCJ clone 27 (BD trnsduction laboratories)and the po lyclonal antibody CD117 (DAKO Cytomation) have been used for the study of the immunohistochemical profile. The optimal diluition of the antibodies were 1:20 for anti-pkcj and 1:400 for anti-cd117. Tumors were scored as positive for PKCJ or CD117 if there was either a diffuse staining or a focal expression in several clusters of cells. Cases with a minimal expression of PKCJ or CD117 in a few single cells (< 10%) were scored as megative. Results. The cases have been classified, according to mitotic activity and neoplasia dimensions, into 3 groups: 1) low malignancy grade GIST (mitotic activity < 5 mitosis x 50 HPF and/or dimensions < 5 cm): 32% (11 out of 35). All the lesions of this group were positive for CD117 (100%); 2) high malignancy grade GIST (mitotic activity > 5 mitosis x 50 HPF and/ or dimensions > 5 cm): 51% (18 out of 35). Immunoreactivity for CD117 has been found in 17 lesions out of 18 (96%); 3) GIST with a clear leyomysarcomatous differentiation: 17% (6 out of 35). All these cases were negative for CD117. PKCJ was positive in 28 out of 29 GIST (96%). All the leyomyosarcomas were negative for PKCJ. The only case classified as GIST, according to histological findings, but CD117 negative, has revealed a good PKCJ expression (40%), with a positivity grade well exceeding the fixed score. Conclusions. The results clearly show that PKCJ undoubtly appears to be a new and further marker of GIST. Unlike CD117, its positivity is not exclusively related to the expression of the KIT receptor tyrosin-kinase activity but to a more transductional pathway, of which the activity attributed to KIT receptor represents only one of the aspects. Therefore, PKCJ is positive even in cases of immuno-phenotypically CD117 negative GIST, which cannot be attributed to the existence of a mutation characterising the KIT receptor expression. As a consequence, the synergic use of two markers makes diagnosis of GIST more accurate. Diagnostic and therapeutic importance of the PKCq expression in Gastrointestinal stromal tumors (GIST): implications resulting from PKCq phosphorylation F. Corini, M. Del Vecchio, A. D Angelo, A. Braccischi, L. Diamanti Section of Anatomic Pathology, C. e G. Mazzoni Hospital, Ascoli Piceno, Italy Introduction. Although selective inhibition of KIT and PDG- FRA receptors activity by means of drugs such as Imatinib has markedly improved the life expectancy of GIST s patients, further markers are being searched for that can act as target for beneficial pharmacological therapies. PKCJ belongs to a family of proteins showing serin/treonin Kinasic activity; it presents numerous characteristics which may suggest its use as therapeutic target in GIST, mostly in those patients with GIST resistant to Imatinib treatment. It is a molecule involved in the transduction of intracellular signals which, in turn, are involved in the regulation of various cellular functions, such as proliferation (reproduction?) secretation, skeletal-muscular differentiation and apoptosis. PKCq is distinctly present in GIST, as researches regarding genic expression have highlighted, and its functionality is regulated by two different events: the activation induced by molecules as diacilglycerol (DAG) and the regulation of cataqlytic activity through phosphorylation of threoninic residue 538 (activation loop), the autophosphorylation of serinic residue 676 (turn motif), the autophosphorylation of serinic residue 695 (idrofobic motif). A methodical analysis of the data resulting from a survey of the mutations engendered by the three main controlling sites: activation loop (Thr 538 ), turn motif (Ser 676 ) and hydrophobic motif (Ser 695 ) concerning catalytic activity and PKCJ phosphorylation, has allowed to identify two distinct regulation modalities of catalytic activity: phosphorylation of the activation loop and hydrophobic motif. The latter, the phosphorylation of the activation loop, plays an important role in the activation of nuclear factor B (NF-kB). Material and methods. Study group. Twenty-eight gastrointestinal tumours (GIST) have been selected: 27 KIT-positive cases and 1 KIT-negative case. The group includes 12 gastric location neoplasia, 11 intestinal location neoplasia, 2 rectum-colic location neoplasia, 1 peritoneal location neoplasia, 1 retro-peritoneal location neoplasia. 1 duodenal location neoplasia.
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