Abstract
The fourth edition of the World Health Organization (WHO) classification of pituitary tumors recommended evaluation of tumor proliferation and invasion to identify aggressiveness. We aimed to assess the prognostic roles of the Ki-67 proliferation index, mitotic index, P53 expression, and cavernous sinus invasion in pituitary adenomas (PAs). Among the 601 patients who underwent transnasal/transsphenoidal adenomectomy from 2001 to 2016, 101 patients (16.8%) who had tumors with a high (≥ 3%) Ki-67 index (group A) and a control group consisting of 43 patients with a low (< 3%) Ki 67 index who were matched for age, gender, and tumor type were included. Mitotic index and P53 expressions were evaluated. Patient characteristics, histopathology reports, pre/postoperative magnetic resonance imaging (MRI), and follow-up data were assessed retrospectively. The frequency of macroadenomas and mean tumor size were greater in group A when compared to group B (67.4 vs. 94.1%, p< 0.01 and 25 ± 10.6 vs. 18 ± 11 mm, p< 0.01, respectively). Invasion to cavernous sinus was found in 53 (36.8%) patients and was more frequent in group A (p<0.01). The mean number of surgery was higher in group A than group B (p< 0.05). The mean follow-up period was 46.6 ± 34 months. The postoperative MRIs and follow-up data for at least 24 months were available in 117 patients. Recurrence risk was higher in group A than group B (p = 0.03). Tumors with high Ki-67 proliferation index were grouped as 3–5, 6–10, 11–15, and > 15%. The risk of recurrence was not different between groups of high Ki-67 index. The optimal cutoff point of the Ki-67 proliferation index that predicted recurrence was 2.5% with 84.6% sensitivity and 47.4% specificity. The cavernous sinus invasion on MRI was associated with recurrence (p = 0.03). Tumor size and recurrence risk were not associated with P53 expression. High P53 expression was related with cavernous sinus invasion (p = 0.03). The mitotic index was not associated with recurrence risk and tumor invasion. Recurrence risk was higher in tumors with ≥ 2 histopathological atypia criteria (p = 0.01). High Ki-67 index with a 2.5% cutoff point and cavernous sinus invasion on MRI are reliable markers for predicting recurrence in PAs. Recurrence risk is also higher in tumors with two histopathological aggressiveness criteria. Strict follow-up and more aggressive treatment approaches may be necessary for invasive-proliferative PAs.
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References
Chatzellis E, Alexandraki KI, Androulakis, II, Kaltsas G (2015) Aggressive pituitary tumors. Neuroendocrinology 101 (2):87–104. doi:https://doi.org/10.1159/000371806
Zaidi HA, Cote DJ, Dunn IF, Laws ER, Jr (2016) Predictors of aggressive clinical phenotype among immunohistochemically confirmed atypical adenomas. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 34:246–251. doi:https://doi.org/10.1016/j.jocn.2016.09.014
Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33 (4):610–617; discussion 617-618
Lloyd RV KK, Young WF, Farrel WE, Asa SL, Truillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E, DeLellis RA, Heitz PU (2004) Pituitary tumors; in WHO Classification of Tumors of the Endocrine Organs: Pathology and Genetics of Endocrine Organs.
Al-Shraim M, Asa SL (2006) The 2004 World Health Organization classification of pituitary tumors: what is new? Acta neuropathologica 111 (1):1–7. doi:https://doi.org/10.1007/s00401-005-1093-6
Chiloiro S, Doglietto F, Trapasso B, Iacovazzo D, Giampietro A, Di Nardo F, de Waure C, Lauriola L, Mangiola A, Anile C, Maira G, De Marinis L, Bianchi A (2015) Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis. Neuroendocrinology 101 (2):143–150. doi:https://doi.org/10.1159/000375448
Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) (2017) WHO classification of tumours of endocrine organs, 4th edn. IARC Press, Lyon.
Ramirez C, Cheng S, Vargas G, Asa SL, Ezzat S, Gonzalez B, Cabrera L, Guinto G, Mercado M (2012) Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: a high throughput TMA, immunohistochemical study. The Journal of clinical endocrinology and metabolism 97 (5):1745–1751. doi:https://doi.org/10.1210/jc.2011-3163
Chiloiro S, Bianchi A, Doglietto F, de Waure C, Giampietro A, Fusco A, Iacovazzo D, Tartaglione L, Di Nardo F, Signorelli F, Lauriola L, Anile C, Rindi G, Maira G, Pontecorvi A, De Marinis L (2014) Radically resected pituitary adenomas: prognostic role of Ki 67 labeling index in a monocentric retrospective series and literature review. Pituitary 17 (3):267–276. doi:https://doi.org/10.1007/s11102-013-0500-6
Knosp E, Kitz K, Perneczky A (1989) Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25 (6):927–930
Madsen H, Borges TM, Knox AJ, Michaelis KA, Xu M, Lillehei KO, Wierman ME, Kleinschmidt-DeMasters BK (2011) Giant pituitary adenomas: pathologic-radiographic correlations and lack of role for p53 and MIB-1 labeling. The American journal of surgical pathology 35 (8):1204–1213. doi:https://doi.org/10.1097/PAS.0b013e31821e8c96
Kim JS, Lee YS, Jung MJ, Hong YK (2016) The Predictive Value of Pathologic Features in Pituitary Adenoma and Correlation with Pituitary Adenoma Recurrence. Journal of pathology and translational medicine 50 (6):419–425. doi:https://doi.org/10.4132/jptm.2016.06.30
de Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C, Katznelson L (2010) Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. Neurological research 32 (10):1060–1071. doi:https://doi.org/10.1179/016164110X12670144737855
Del Basso De Caro M, Solari D, Pagliuca F, Villa A, Guadagno E, Cavallo LM, Colao A, Pettinato G, Cappabianca P (2017) Atypical pituitary adenomas: clinical characteristics and role of ki-67 and p53 in prognostic and therapeutic evaluation. A series of 50 patients. Neurosurgical review 40 (1):105–114. doi:https://doi.org/10.1007/s10143-016-0740-9
Zakir JC, Casulari LA, Rosa JW, Rosa JW, de Mello PA, de Magalhaes AV, Naves LA (2016) Prognostic Value of Invasion, Markers of Proliferation, and Classification of Giant Pituitary Tumors, in a Georeferred Cohort in Brazil of 50 Patients, with a Long-Term Postoperative Follow-Up. International journal of endocrinology 2016:7964523. doi:https://doi.org/10.1155/2016/7964523
Raverot G, Dantony E, Beauvy J, Vasiljevic A, Mikolasek S, Borson-Chazot F, Jouanneau E, Roy P, Trouillas J (2017) Risk of Recurrence in Pituitary Neuroendocrine Tumors: A Prospective Study Using a Five-Tiered Classification. The Journal of clinical endocrinology and metabolism 102 (9):3368–3374. doi:https://doi.org/10.1210/jc.2017-00773
Mastronardi L, Guiducci A, Puzzilli F (2001) Lack of correlation between Ki-67 labelling index and tumor size of anterior pituitary adenomas. BMC cancer 1:12
Lv L, Hu Y, Yin S, Wang M, Zhou P, Zhang N, Ma W, Zhang S, Jiang S (2018) Clinically aggressive phenotype: A clinicopathological case series of atypical pituitary adenomas. Clinical neurology and neurosurgery 167:93–98. doi:https://doi.org/10.1016/j.clineuro.2018.02.001
Gejman R, Swearingen B, Hedley-Whyte ET (2008) Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Human pathology 39 (5):758–766. doi:https://doi.org/10.1016/j.humpath.2007.10.004
Chacko G, Chacko AG, Kovacs K, Scheithauer BW, Mani S, Muliyil JP, Seshadri MS (2010) The clinical significance of MIB-1 labeling index in pituitary adenomas. Pituitary 13 (4):337–344. doi:https://doi.org/10.1007/s11102-010-0242-7
Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D, Laws ER, Jr. (1996) Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38 (1):99–106; discussion 106-107
Honegger J, Prettin C, Feuerhake F, Petrick M, Schulte-Monting J, Reincke M (2003) Expression of Ki-67 antigen in nonfunctioning pituitary adenomas: correlation with growth velocity and invasiveness. Journal of neurosurgery 99 (4):674–679. doi:https://doi.org/10.3171/jns.2003.99.4.0674
Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws ER, Jr. (1996) p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 38 (4):765–770; discussion 770-761
Ozer E, Canda MS, Ulukus C, Guray M, Erbayraktar S (2003) Expression of Bcl-2, Bax and p53 proteins in pituitary adenomas: an immunohistochemical study. Tumori 89 (1):54–59
Oliveira MC, Marroni CP, Pizarro CB, Pereira-Lima JF, Barbosa-Coutinho LM, Ferreira NP (2002) Expression of p53 protein in pituitary adenomas. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 35 (5):561–565
Hadzhiyanev A, Ivanova R, Nachev E, Elenkova A, Yaneva M, Zaharieva S, Marinov M, Surchev J, Ivanova A (2014) Evaluation of prognostic utility of MIB-1 and p53 expression in pituitary adenomas: correlations with clinical behaviour and follow-up results. Biotechnology, biotechnological equipment 28 (3):502–507. doi:https://doi.org/10.1080/13102818.2014.932510
Miermeister CP, Petersenn S, Buchfelder M, Fahlbusch R, Ludecke DK, Holsken A, Bergmann M, Knappe HU, Hans VH, Flitsch J, Saeger W, Buslei R (2015) Histological criteria for atypical pituitary adenomas - data from the German pituitary adenoma registry suggests modifications. Acta neuropathologica communications 3:50. doi:https://doi.org/10.1186/s40478-015-0229-8
Lee EH, Kim KH, Kwon JH, Kim HD, Kim YZ (2014) Results of immunohistochemical staining of cell-cycle regulators: the prediction of recurrence of functioning pituitary adenoma. World neurosurgery 81 (3–4):563–575. doi:https://doi.org/10.1016/j.wneu.2013.09.035
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The study was approved by local Ethical Committee of Ankara University Faculty of Medicine (April, 2016, 07-296-16).
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Hasanov, R., Aydoğan, B.İ., Kiremitçi, S. et al. The Prognostic Roles of the Ki-67 Proliferation Index, P53 Expression, Mitotic Index, and Radiological Tumor Invasion in Pituitary Adenomas. Endocr Pathol 30, 49–55 (2019). https://doi.org/10.1007/s12022-018-9563-2
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DOI: https://doi.org/10.1007/s12022-018-9563-2