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Bertozzi, Irene (2017) Biomolecular and histological features in pediatric essential thrombocythemia: adequacy of who diagnostic criteria. [Ph.D. thesis]

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Abstract (english)

Myeloproliferative neoplasms (MPN), Essential Thrombocythemia (ET), Polycythemia Vera (PV) and primary myelofibrosis (PMF), are clonal disorders of the hematopoietic stem cell. In the recent years, somatic mutations of JAK2, CALR and MPL genes have been found in these diseases. However, these mutations do not allow the discrimination between the different diseases, being present in more than one form. World Health Organization (WHO) criteria, in fact, request in addition to the molecular study, a complete bone marrow histological evaluation. Pediatric ET is a rare disorder with an incidence about 60 times lower than the adult form albeit with similar blood finds. In children with ET, the incidence of JAK2V617F and CALR mutations is significantly lower than in adults, while hereditary cases characterized by MPL mutations are relatively more common. So far the histological evaluation of the bone marrow has not been exhaustively explored in this setting of patients.
The aim of the present study was to evaluate the adequacy of current WHO criteria in pediatric ET exploring both the incidence of driver mutations and bone marrow features in a large cohort of children with a clinical diagnosis of ET.
Our study was built in two steps: (i) a biomolecular study of a pediatric population with a clinical diagnosis of ET performed by Italian pediatricians, expert in hematological disorders and (ii) a histological evaluation strictly adherent to WHO criteria of BM features of a sub group of these children. Firstly, biomolecular studies of 89 children with a clinical diagnosis of ET, all having a sustained increase in platelet count (>450 x10^9/L) with no demonstrable reactive or secondary cause and no familial history of MPN or thrombocytosis, were evaluated to our central laboratory. In the second phase of our work we collected naïve bone marrow (BM) biopsies of 20 children with a clinical diagnosis of ET (PedET) and, as controls, BM of 6 children (PedST) with reactive/secondary thrombocytosis, 18 children (Norm) with a normal BM histology and 36 adults (AdsET) with WHO-diagnosed ET. All BM biopsies were reviewed by two MPN’s expert pathologists, blinded to the cause of each child’s thrombocytosis.
In the biomolecular study we found that 23 patients (25,8%) had a clonal disease. The JAK2V617F mutation was identified in 14 children, 1 child had the MPLW515L mutation, and 6 had CALR mutations. The HUMARA monoclonal X-chromosome inactivation pattern was demonstrate in 6 patients (two with JAK2V617F and two with CALR mutations). The other 66 patients (74,2%) had persistent thrombocytosis with no clonality. There were no clinical or hematological differences between the clonal and non-clonal patients.
From the histological point of view, while cellularity was increased in all pediatric cases compared to adults (p<0.001), megakaryocytes (MK) density was higher in PedET (37.5 MK/mm2) than in PedST (9.2 MK/mm2) (p<0.001). Moreover, MK clusters (100%) and BM fibrosis (30%) were observed only in PedET but not in PedST and in Norm. The BM histology was similar in PedET and AdsET. On a whole, BM histology confirmed the diagnosis of ET in 15 children, suggested a PV in 1 child, a PMF in 3 (1 grade 1 and 2 grade 0) and secondary thrombocytosis in one.
Our study shows that children with ET are mostly non-clonal, however, the relative proportion of ET-specific mutations in the clonal children was much the same as in adults. Histological WHO criteria are able to identify ET, PMF and PV and distinguish ST from primary thrombocytosis, also in pediatric population. Therefore, WHO criteria seem suitable in all age groups, making both complete biomolecular evaluation and BM assessment mandatory in children with suspected ET.

Abstract (italian)

Le Neoplasie Mieloproliferative (MPN), sono disordini clonali della cellula staminale emopoietica, caratterizzate dalla proliferazione di una o più linee mieloidi e sono Trombocitemia Essenziale (ET), Policitemia Vera (PV) e Mielofibrosi Idiopatica (PMF). I criteri diagnostici per le MPN dell’adulto si sono evoluti nel tempo di pari passo con l’acquisizione di nuove conoscenze clinico-laboratoristiche e biomolecolari di tali patologie. Negli ultimi anni sono state descritte mutazioni somatiche a carico dei geni JAK2, CALR e MPL, tuttavia queste mutazioni non consentono una distinzione accurata in quanto presenti in più di una MPN. Nei più recenti criteri diagnostici WHO, di conseguenza, accanto allo studio biomolecolare, è necessaria una completa valutazione della biopsia osteo-midollare (BOM).
La ET pediatrica è una malattia rara con un’incidenza stimata di circa 60 volte inferiore alla forma dell’adulto. L’incidenza delle mutazioni di JAK2 e di CALR è significativamente inferiore nei bambini con ET rispetto agli adulti, mentre sono relativamente più numerosi i casi ereditari caratterizzati da mutazioni di MPL. Ad oggi in questi pazienti non è stata ancora esplorata esaustivamente la rilevanza della valutazione istologica del midollo.
Lo scopo del nostro studio è stato quello di verificare l’adeguatezza dei criteri WHO nella popolazione pediatrica esplorando sia l'incidenza delle mutazioni principali che le caratteristiche della BOM in un'ampia casistica di bambini con diagnosi clinica di ET.
Il nostro lavoro è stato costruito in due momenti: (i) uno studio biomolecolare in bambini con diagnosi clinica di ET fatta da Pediatri Italiani esperti in disordini ematologici e (ii) una valutazione istologica della BOM in un sottogruppo di questi bambini, applicando rigorosamente i criteri WHO.
Nella prima parte dello studio abbiamo valutato 89 bambini con diagnosi clinica di ET con un incremento prolungato della conta piastrinica (>450 x10^9/L) in assenza di cause secondarie o reattive e senza familiarità per MPN o trombocitosi. I campioni stati sono stati centralizzati presso il nostro laboratorio per lo studio biomolecolare completo. Nella seconda fase, abbiamo collezionato le BOM di 20 bambini con diagnosi clinica di ET (PedET) e, come controlli, di 6 bambini con trombocitosi reattiva (PedST), 18 bambini (Norm) con istologia midollare nella norma e 36 adulti con diagnosi di ET in accordo con in criteri WHO (AdsET). Tutte le BOM sono state rilette in cieco da due patologi esperti in MPN.
Nello studio biomolecolare in 23 pazienti (25,8%) è stata dimostrata la presenza di un marker di clonalità: 14 bambini erano positivi per la mutazione JAK2V617F, 1 bambino aveva la mutazione MPLW515L e 6 avevano mutazioni di CALR. Inoltre, sei pazienti sono risultate clonali allo studio dell’inattivazione del cromosoma X (due portatrici anche la mutazione JAK2V617F e due con mutazioni di CALR). Gli altri 66 pazienti (74,2%) presentavano una trombocitosi persistente senza evidenza di clonalità. Non sono state dimostrate differenze clinico-ematologiche tra i pazienti clonali e non clonali.
Dal punto di vista istologico, la cellularità è risultata più alta in tutti i casi pediatrici rispetto agli adulti (p <0.001), mentre la densità megacariocitaria (MK) è risultata più alta nei PedET (37,5 MK/mm2) rispetto a PedST (9.2 MK/mm2) (p <0,001). Inoltre, i cluster di MK (100%) e la fibrosi midollare (30%) sono stati osservati solo in PedET, essendo sostanzialmente assenti sia in PedST che Norm. L’istologia della BOM è risultata pressoché sovrapponibile in PedET e AdsET. Tra i bambini con PedET, l’istologia della BOM ha confermato in 15 casi la diagnosi di ET, in 1 caso è risultata suggestiva per PV, in 3 casi per PMF (1 grado 1 e 2 grado 0) ed in un caso per trombocitosi secondaria.
Il nostro studio conferma che, sebbene la maggior parte dei bambini non presenti un marker di clonalità, le mutazioni classiche delle MPN sono presenti anche nella ET pediatrica con una proporzione simile a quella delle forme dell’adulto. I criteri istologici WHO sono in grado, anche nella popolazione pediatrica, di identificare ET, PV e PMF e di distinguere forme primitive e secondarie di trombocitosi.
In conclusione, i criteri WHO sembrano adeguati per tutte le fasce d’età. Ciò impone una completa valutazione biomolecolare ed istologica anche nei bambini con sospetta ET.

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EPrint type:Ph.D. thesis
Tutor:Randi, Maria Luigia
Ph.D. course:Ciclo 29 > Corsi 29 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI
Data di deposito della tesi:13 January 2017
Anno di Pubblicazione:13 January 2017
Key Words:Neoplasie mieloproliferatve pediatriche/Pediatric MPN Trombocitemia Essenziale/Essential Thrombocythemia Mutazioni JAK2 CALR MPL/JAK2 CLAR MPL mutations Istologia del midollo osseo nella ET/BM histology in ET
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:9842
Depositato il:14 Nov 2017 12:21
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