Klinička važnost otkrivanja proliferacijskih i antiproliferacijskih pokazatelja ljudskih meningeoma

Forempoher, Gea (2005) Klinička važnost otkrivanja proliferacijskih i antiproliferacijskih pokazatelja ljudskih meningeoma. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Biopsy specimens from 102 meningiomas were formalin fixed, paraffin-embedded and H&E stained. All samples were analysed by flow cytometry to determine ploidy level and perform cell-cycle analysis. All samples were immunostained for PCNA and p53 protein expression. On H&E stained slides we analysed histological parameters such as cellularity, number of mitoses, necrosis and cellular atypia. According to the 1993 WHO criteria, revised by Perry et al., 102 meningiomas were classified into grade I=49 benign meningiomas, grade II=30 atypical meningiomas, grade III=23 malignant meningiomas. The patients were divided in two groups, according to the absence (N=30) or presence (N=36) of recurrence, and the third group of patients with diagnose of atypical/malignant meningioma at first biopsy (N=12). The patients were followed from 5 to 12 years (for an average of 88.4 ± 35.7months). We did not find any statistically significant relation when sex, age and prognosis were considered. Histological grade was significantly associated with prognosis. There were statistically satisfactory higher number of meningiomas with histological grade II and III in the recurrence group (p=0.000). In fact in the recurrence group there were respectively 31% of grade I meningiomas, 46% of grade II and 23% of grade III meningiomas. In the control group of nonrecurrent meningiomas there were no grade tumors III, 90% were benign and 10% atypical meningiomas. Histological features of benign meningiomas which significantly correlated with recurrence were celular polymorphism, nuclear atypia, sheeting and high cellularity (>53). DNA aneuploidy was significantly higher in recurrent meningiomas 37% (13/35) compared to the nonrecurrent meningioma group 7% (2/30). In the group of histologically benign recurrent meningiomas 45% were aneuploid (5/11) compared to only one aneuploid tumor (4%) in benign nonrecurrent meningioma group. DNA ploidy is useful indicator of different biological behaviour within identical histological subgroup in meningeoma. There were no statically significant differences in the S-phase fraction values compared with other parameters. The percentage of PCNA positively stained cells was correlated with histological features and histological grade. Correlation between number of mitosis and PCNA was statistically significant (p=0.016). Correlation between histological grade and PCNA expression was statistically significant and expression was increasing with histological grade (p=0.032). The expression of p53 was significantly higher in recurrent meningioma group (p=0.003). Expression of p53 >20% was found in 66% of recurrent meningiomas. In benign recurrent meningeoma group 45% of meningiomas (5/11) had expression of p53>20%, compared to 81% of meningiomas without or with low expression of p53 in benign nonrecurrent meningioma group (22/27). In the group of 102 meningiomas statistically significant correlation was found between the p53 expression and histological grade (p=0.000).

Abstract in Croatian

Bioptički uzorci 102 meningeoma su fiksirani formalinom, uklopljeni u parafin i bojani hemalaun-eozinom (HE). Svi uzorci analizirani su metodom protočne citometrije kojom se odredilo proliferativnu aktivnost i ploidiju. Usporedno, svi su tumori analizirani s pomoću imunohistokemijskog bojenja na izražaj dvaju biljega: biljega proliferacije PCNA i produkta-tumor supresijskog gena p53. Na HE bojenim preparatima ispitivane su histološke značajke koje uključuju celularnost, broj mitoza, područja nekroze i stupanj atipije stanica. Po standardima Svjetske zdravstvene organizacije iz 1993. god. revidiranoj po Perry-u i sur., meningeome smo klasificirali u tri stupnja: benigne (N=49), atipične (N=30) i anaplastične (N=23). Analiziran je bioptički materijal bolesnika s dijagnozom meningeoma na prvoj operaciji (N=66). Od toga u 36 bolesika nastupio je recidiv bolesti. Ostali bolesnici kod kojih nije došlo do recidiva bolesti (N=30) predstavljali su kontrolnu skupinu. Bolesnici su praćeni su od 5 do 12 god. (srednje vrijeme praćenja 88.4±35.7 mjeseci). Usporedno je analiziran bioptički materijal bolesnika s postavljenom dijagnozom atipičnog/malignog meningeoma već pri prvom operativnom zahvatu (N=12). Nije bilo razlike u preživljenju za dob niti između grupe muškaraca i žena. Histološki stupanj meningeoma povezan je s prognozom. Značajno veći broj meningeoma histološkog stupnja II i III nalazi se u grupi recidiva u odnosu na tumore kontrolne skupine koji nisu razvili recidiv u promatranom periodu (p=0.000). U grupi recidiva bilo je 31% meningeoma I. stupnja, 46% meningeoma II. stupnja i 23% meningeoma III. stupnja. U kontrolnoj skupini meningeoma koji nisu recidivirali nije bilo malignih tumora, atipičnih je bilo 10% (3/30), a benignih 90% (27/30). Od histoloških značajki u grupi benignih meningeoma koji će recidivirati postoji statistički značajno više izražen pleomorfizam stanica, atipija jezgara, gubitak strukture i povećana celularnost (>53). Aneuploidija je bila značajno više zastupljena u grupi recidiva 37% (13/35) u odnosu na samo 7% aneuploidnih meningeoma (2/30) među onima koji nisu imali recidiv. U grupi histološki benignih meningeoma koji nisu recidivirali samo je jedan aneuploidni histogram (4%). U grupi histološki benignih recidiva 45% meningeoma je imalo aneuploidni histogram (5/11). Stoga smatramo da je svaka aneuploidija znak lošijeg biološkog ponašanja i koristan pokazatelj budućeg recidiva. Postotak stanica u S-fazi nije postigao statistički značaj prilikom korelacije sa ispitivanim značajkama. Visoka izraženost PCNA statistički je značajno povezana s brojem mitoza (p=0.016). Na ukupno 102 analizirana meningeoma stupanj izraženosti PCNA se statistički razlikovao među meningeomima različitig stupnja i rastao je s histološkim stupnjem meningeoma (p=0.032). U grupi recidiva čak 66% meningeoma imalo je srednji i visoki izražaj p53 i taj je ujedno statistički značajno viši od izražaja p53 u meningeoma koji nisu recidivirali (p=0.003). U grupi recidiva benigne histologije 45% je imalo srednji i visoki izražaj p53 (5/11). U nerecidivnim meningeomima benigne histologije 81% tumora su bili bez ili s niskim izražajem p53 (22/27). Na ukupno 102 analizirana meningeoma stupanj izraženosti p53 se značajno statistički razlikovao za meningeome različitig histološkog stupnja (p=0.000).

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