Pretkazatelji kliničkoga ponašanja adenoma hipofize [Predictors of clinical behavior of pituitary adenomas]

Solak, Mirsala (2018) Pretkazatelji kliničkoga ponašanja adenoma hipofize [Predictors of clinical behavior of pituitary adenomas]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

The aim of this study was to investigate the expression of histological markers Ki-67, p53 and mitotic activity in pituitary adenomas and their correlation with the frequency of recurrence and progression of residual adenoma. Additional purpose of the study was the analysis of clinical course after operative treatment for a period of at least five years, and analysis of proliferative markers depending on the type and clinical behavior of pituitary adenoma. The study comprised 94 patients operated due to pituitary adenoma in the period from 2005 to 2011, who were treated at the Department of Endocrinology, University Hospital Center Zagreb. After the operation, 63.8% of patients had residual adenoma. In the minority of patients (12/60 patients, 20%) with residual adenoma we detected increase in size. In patients with complete adenoma resection, only few patienst had recurrence (3/34 patients, 8.8%). The analysis showed that the adenoma size had a significant prognostic value for residual tumor (p=0.027). In majority of adenoma samples (74.5%) expression of Ki-67 was less than 3%, 26.1% had positive p53 while only 9.6% had mitotic activity. Functional adenomas had significantly higher expression of Ki-67 compared to nonfunctional adenomas (p=0.012). The expression of the Ki-67 in the pituitary adenoma correlated positively with the recurrence of adenoma as well as the increase in residual adenoma (p<0.001). On the other hand, the expression of p53 and mitotic activity in adenoma tissue did not correlate with the recurrence or increase of residual adenoma (p=0.201 and p=0.26, respectively). Cut-off value of Ki-67 ≥3% was significant for the time of residual adenoma progression or adenoma recurrence after complete removal (p=0.007). All patients with residual adenoma, regardless of the clinical outcome, had a significantly higher expression of Ki-67 compared to patients without residue (p=0.009). Patients with residual adenomas had significantly larger and more invasive adenomas (p<0.001 and p=0.002, respectively). In patients with enlargement of residual adenoma or recurrence after complete removal, the expression of Ki-67 was higher compared to patients with stable residue or complete adenoma removal (p<0.001). Patients with increased residue size and recurrent adenomas had significantly larger initial size of the adenoma (p=0.045). Moreover, these patients had higher expression of Ki-67 compared only to the group of patients with stable residue (p=0.005). Based on this study we can conclude that patients with larger adenoma size and higher expression of proliferative marker Ki-67 should be monitored more closely because they have an increased chance of progression of residual adenoma or recurrence after complete removal.

Abstract in Croatian

Cilj ovog istraživanja bio je ispitivanje ekspresije histoloških markera Ki-67, p53 i mitotske aktivnosti u adenomima hipofize te njihova korelacija s učestalošću recidiva odnosno progresije veličine ostatnog adenoma. Dodatni cilj bio je analiza kliničkog tijeka nakon operativnog liječenja tih bolesnika u razdoblju od pet godina te analiza proliferacijskih markera ovisno o tipu i kliničkom ponašanju adenoma hipofize. U istraživanje je uključeno 94 bolesnika operiranih zbog adenoma hipofize u razdoblju od 2005. do 2011. godine koji su praćeni najmanje pet godina u Zavodu za endokrinologiju KBC Zagreb. Neurokirurškim zahvatom u 63,8% bolesnika nije bilo moguće odstraniti adenom u cijelosti i zaostaje rezidua. Kod manjine bolesnika s rezidualnim adenomom (12/60 bolesnika, 20%) došlo je do porasta veličine rezidue. Kod bolesnika kojima je adenom ostranjen u cjelosti vrlo rijetko su se tijekom petogodišnjeg praćenja javljali recidivi (3/34 bolesnika, 8,8%). Pokazano je da veličina adenoma ima prognostičku važnost za postojanje rezidue nakon operativnog zahvata (p=0,027). U većine adenoma hipofize (74,5%) ekspresija Ki-67 je bila manja od 3%. Manjina adenoma hipofize (26,1%) pokazivala je pozitivitet na p53, a mitotska je aktivnost bila vidljiva u 9,6% adenoma. Funkcionalni adenomi hipofize imali su značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s nefunkcionalnim adenomima (p=0,012). Ekspresija proliferacijskog markera Ki-67 u adenomu hipofize je pozitivno korelirala s pojavom recidiva adenoma kao i s porastom veličine rezidualnog adenoma (p<0,001). S druge strane, ekspresija histološkog markera p53 kao i mitotska aktivnost u tkivu adenoma nisu korelirale s pojavom recidiva niti s porastom rezidualnog adenoma (p=0,201 i p=0,26). U ovom istraživanju je pokazano da kod prijelomne vrijednosti Ki-67 ≥3% postoji razlika u vremenu do progresije rezidue odnosno pojave recidiva adenoma (p=0,007). Svi bolesnici s rezidualnim adenomom, neovisno o kliničkom tijeku rezidue, su tijekom praćenja imali značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s bolesnicima bez rezidue (p=0,009). Bolesnici s reziduom su imali značajno veći i invazivniji adenom (p<0,001 i p=0,002). U bolesnika kod kojih je došlo do porasta rezidualnog adenoma ili se pojavio recidiv tijekom praćenja, ekspresija Ki-67 je bila veća nego kod bolesnika sa stabilnom reziduom i bez rezidue (p<0,001). Bolesnici s rastućom reziduom i recidivom adenoma su pri postavljanju dijagnoze imali značajno veći adenom (p=0,045). Ovi bolesnici su, također, imali veću ekspresiju Ki-67 u usporedbi samo s bolesnicima sa stabilnim rezidualnim adenomom (p=0,005). Na temelju ovog istraživanja možemo zaključiti da bolesnike s većim adenomom hipofize i većom ekspresijom proliferacijskog markera Ki-67 treba pomnije pratiti jer imaju povećanu šansu za progresiju rezidualnog adenoma ili pojavu recidiva nakon kompletnog odstranjenja.

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