Background - Chondrosarcomas (CS) of the bone are a rare heterogeneous group of cartilaginous matrix-producing neoplasm. Conventional CS represents the most frequent subtype and is histologically classified into low (G1), intermediate (G2) and high grade (G3). Low-grade CS are considered locally aggressive neoplasm with minimal risk of metastasis, whereas intermediate and especially high grade CS are malignant neoplasms characterized by high rates of local recurrence and metastasis, with a worse prognosis on survival. Chondrosarcoma is generally considered chemo and radioresistant due to the low growth rate, and surgery remains the only curative approach for localized forms, while for advanced forms of disease the prognosis is poor. Mutations in the IDH1/2 genes, coding for 2 isoforms of isocitrate dehydrogenase, are present in various malignant tumors, including gliomas and secondary glioblastomas, acute myeloid leukemia, and cholangiocarcinoma, and their prognostic role has been investigated. Recently. IDH1/2 mutations have been found in about 50% of conventional central CS and up to 80% of dedifferentiated CS; however, there are conflicting results in the literature about the negative impact on survival that these mutations may have. The purpose of this study is to evaluate the incidence of IDH mutations in CSs and to study the clinical outcomes of patients in relation to IDH mutational status, in order to show the prognostic role these mutations may have. Materials and Methods - 45 new patients with a histological diagnosis of CS who were surgically treated in our center from 2017 to 2020 were enrolled in a prospective study. All cases were evaluated by two expert bone and soft tissue pathologists and the grading was assigned according to the current WHO 2020 classification. DNA was extracted from five 10-µm paraffin-embedded sections using the QIAmp FFPE tissue Kit (Qiagen) and quantified using the Qubit® 3.0 fluorometer and the Qubit® DNA BR Assay kit (Thermo Fisher Scientific) for each patient. Then mutational status of IDH1 (codons 105 and 132) and IDH2 (codons 140 and 172) genes was assessed using an EasyPGX-ready IDH1-2 kit. For each reaction, 15.30 ng of DNA was used. The results were examined using EasyPGX analysis software. Results - IDH mutational status could only be evaluated in 23 cases; this series includes: 10 males and 13 females, with a mean age of 56 years (range, 15-98 years). There were 22 conventional CS (8 grade 1, 11 grade 2, 3 grade 3) and 1 dedifferentiated CS. 17 patients harbored IDH1/2 mutation (12 IDH1 R132, 3 IDH1 G105 and 2 IDH2 R172), while 6 patients showed wild-type IDH. Interestingly, the IDH1 R132 was found in all grades of conventional CS and dedifferentiated CS. No patient was lost to follow-up. At a mean follow-up of 3.5 years (range, 4 months – 5.6 years), 13 patients were disease free, 3 alive with disease and 8 died. Metastasis occurred in 7 cases and local recurrence in 7 cases. Overall survival was 87% and 61% at 2 and 4 years, respectively. Correlating IDH1/2 mutational status with patient outcome, patients with the IDH1 R132 mutation had significantly lower overall survival (p = 0.0015), metastasis-free survival (p=0.001), and recurrence-free survival (p= 0.0235) compared with patients with the other mutations and wild-type IDH. Conclusion - We found that IDH1 R132 mutations negatively affect the prognosis of patients with bone CS, highlighting how they may play a role in disease progression and the occurence of metastasis, resulting in patients death. Molecular analysis of IDH mutational could be useful for better stratification of patients with the disease, thus enabling better therapeutic management of patients and closer follow-up. Of course, these preliminary results were obtained on a limited case series and must necessarily be confirmed in larger series.
Introduzione - I condrosarcomi (CS) dell’osso sono un insieme di rare neoplasie eterogenee caratterizzate dalla produzione di matrice cartilaginea. Il condrosarcoma convenzionale rappresenta il sottotipo più frequente ed è classificato istologicamente in basso (G1), intermedio (G2) e alto grado (G3). I condrosarcomi di basso grado sono considerati neoplasie localmente aggressive, con un minimo rischio di metastatizzazione, mentre i condrosarcomi di intermedio e soprattutto di alto grado sono neoplasie maligne caratterizzate da alti tassi di recidiva locale e di metastasi, con una prognosi peggiore sulla sopravvivenza. Mutazioni nei geni IDH1/2, codificanti per 2 isoforme di isocitrato deidrogenasi, sono presenti in varie neoplasie, tra cui gliomi e glioblastomi secondari, leucemia mieloide acuta e colangiocarcinoma, ed il loro ruolo prognostico è stato investigato. Recentemente, sono state riscontrate mutazioni di IDH1/2 in circa il 50% dei CS convenzionali centrali e fino all’80% dei CS dedifferenziati; tuttavia, vi sono risultati contrastanti in letteratura circa l’impatto negativo sulla sopravvivenza che queste mutazioni possono avere. Lo scopo di questo studio è quello di valutare l’incidenza delle mutazioni di IDH nei CS e studiare gli esiti clinici dei pazienti in relazione allo stato mutazionale di IDH, così da chiarire meglio il ruolo prognostico che queste mutazioni possiedono. Materiali e metodi - Sono stati arruolati in uno studio prospettico 45 nuovi pazienti con diagnosi istologica di CS, trattati chirurgicamente nel nostro centro dal 2017 al 2020. Tutti i casi sono stati valutati da due esperti di tumori dell’osso e dei tessuti molli ed il grading è stato assegnato in accordo con la corrente classificazione WHO 2020. Il DNA è stato estratto da 5 sezioni di 10 µm incluse in paraffina di ogni paziente utilizzando il kit per tessuti QIAmp FFPE (Qiagen) e quantificato utilizzando il fluorimetro Qubit® 3.0 e il kit Qubit® DNA BR Assay (Thermo Fisher Scientific). Lo stato mutazionale dei geni IDH1 (codoni 105 e 132) e IDH2 (codoni 140 e 172) è stato valutato mediante l’utilizzo del kit EasyPGX-ready IDH1-2. Per ogni reazione, sono stati utilizzati 15-30 ng di DNA. I risultati sono stati analizzati con il software di analisi EasyPGX. Risultati – È stato possibile valutare lo stato mutazionale di IDH solamente in 23 casi; questa serie include: 10 maschi e 13 femmine, con un età media di 56 anni (range, 15-98 anni). Sono stati diagnosticati sul campione operatorio finale 22 CS convenzionali (8 grado 1, 11 grado 2, 3 grado 3) e 1 CS dedifferenziato. Mutazioni di IDH1/2 sono state riscontrate in 17 pazienti (12 IDH1 R132, 3 IDH1 G105, 2 IDH2 R172) mentre 6 pazienti hanno mostrato IDH1/2 wild-type. In particolare, la mutazione IDH1 R132 è stata riscontrata in tutti i gradi di CS convenzionale e nel singolo caso di CS dedifferenziato. Nessun paziente è stato perso durante il follow-up. Ad un follow-up medio di 3.5 anni (range, 4 mesi – 5.6 anni), 13 pazienti erano vivi senza malattia, 3 vivi con malattia e 7 sono deceduti. Metastasi polmonari sono insorte in 8 pazienti, di cui 1 alla diagnosi, e recidiva locale in 7. La sopravvivenza globale dei pazienti a 2 e a 4 anni è stata rispettivamente dell’87% e del 61%. Correlando lo stato mutazionale di IDH1/2 all’esito dei pazienti, è risultato che i pazienti con la mutazione IDH1 R132 hanno una significativamente ridotta sopravvivenza globale (p = 0.0031), sopravvivenza libera da metastasi (p = 0.001) e sopravvivenza libera da recidiva locale (p = 0.0235) rispetto ai pazienti con le rimanenti mutazioni e con IDH wild-type. Conclusioni - Abbiamo riscontrato che la mutazione IDH1 R132 ha un impatto decisamente negativo sulla sopravvivenza del paziente affetto da condrosarcoma, evidenziando come possa avere un ruolo nella progressione di malattia e nella comparsa di metastasi, con conseguente morte del paziente.
Condrosarcoma primitivo dell'osso: significato prognostico della mutazione del gene IDH1
SCHIAVOLIN, MATTIA
2022/2023
Abstract
Background - Chondrosarcomas (CS) of the bone are a rare heterogeneous group of cartilaginous matrix-producing neoplasm. Conventional CS represents the most frequent subtype and is histologically classified into low (G1), intermediate (G2) and high grade (G3). Low-grade CS are considered locally aggressive neoplasm with minimal risk of metastasis, whereas intermediate and especially high grade CS are malignant neoplasms characterized by high rates of local recurrence and metastasis, with a worse prognosis on survival. Chondrosarcoma is generally considered chemo and radioresistant due to the low growth rate, and surgery remains the only curative approach for localized forms, while for advanced forms of disease the prognosis is poor. Mutations in the IDH1/2 genes, coding for 2 isoforms of isocitrate dehydrogenase, are present in various malignant tumors, including gliomas and secondary glioblastomas, acute myeloid leukemia, and cholangiocarcinoma, and their prognostic role has been investigated. Recently. IDH1/2 mutations have been found in about 50% of conventional central CS and up to 80% of dedifferentiated CS; however, there are conflicting results in the literature about the negative impact on survival that these mutations may have. The purpose of this study is to evaluate the incidence of IDH mutations in CSs and to study the clinical outcomes of patients in relation to IDH mutational status, in order to show the prognostic role these mutations may have. Materials and Methods - 45 new patients with a histological diagnosis of CS who were surgically treated in our center from 2017 to 2020 were enrolled in a prospective study. All cases were evaluated by two expert bone and soft tissue pathologists and the grading was assigned according to the current WHO 2020 classification. DNA was extracted from five 10-µm paraffin-embedded sections using the QIAmp FFPE tissue Kit (Qiagen) and quantified using the Qubit® 3.0 fluorometer and the Qubit® DNA BR Assay kit (Thermo Fisher Scientific) for each patient. Then mutational status of IDH1 (codons 105 and 132) and IDH2 (codons 140 and 172) genes was assessed using an EasyPGX-ready IDH1-2 kit. For each reaction, 15.30 ng of DNA was used. The results were examined using EasyPGX analysis software. Results - IDH mutational status could only be evaluated in 23 cases; this series includes: 10 males and 13 females, with a mean age of 56 years (range, 15-98 years). There were 22 conventional CS (8 grade 1, 11 grade 2, 3 grade 3) and 1 dedifferentiated CS. 17 patients harbored IDH1/2 mutation (12 IDH1 R132, 3 IDH1 G105 and 2 IDH2 R172), while 6 patients showed wild-type IDH. Interestingly, the IDH1 R132 was found in all grades of conventional CS and dedifferentiated CS. No patient was lost to follow-up. At a mean follow-up of 3.5 years (range, 4 months – 5.6 years), 13 patients were disease free, 3 alive with disease and 8 died. Metastasis occurred in 7 cases and local recurrence in 7 cases. Overall survival was 87% and 61% at 2 and 4 years, respectively. Correlating IDH1/2 mutational status with patient outcome, patients with the IDH1 R132 mutation had significantly lower overall survival (p = 0.0015), metastasis-free survival (p=0.001), and recurrence-free survival (p= 0.0235) compared with patients with the other mutations and wild-type IDH. Conclusion - We found that IDH1 R132 mutations negatively affect the prognosis of patients with bone CS, highlighting how they may play a role in disease progression and the occurence of metastasis, resulting in patients death. Molecular analysis of IDH mutational could be useful for better stratification of patients with the disease, thus enabling better therapeutic management of patients and closer follow-up. Of course, these preliminary results were obtained on a limited case series and must necessarily be confirmed in larger series.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/47449