Abstract
Pituitary neuroendocrine tumours (PitNETs) cause lifelong morbidity, some requiring extensive surgical intervention, radiotherapy, or chemotherapy. A small percentage still cause debilitating disease, resistant to standard treatments, and may benefit from novel therapies. We assessed PD-L1 expression in a large cohort of PitNETs to investigate whether immunotherapy could represent a rational therapeutic choice. Unselected PitNETs undergoing surgical resection were reclassified according to the WHO 2017 system and underwent PD-L1 immunohistochemistry (clone SP263) in tissue microarray format. Membranous expression was scored as 0 (no expression), 1+ (< 50% expression) and 2+ (> 50% expression). A total of 265 PitNETs underwent PD-L1 immunohistochemistry. Prominent non-specific cytoplasmic staining was noted making assessment of true membrane expression difficult. Allowing for this, 40 of 264 (15%) PitNETs demonstrated strong staining (> 50% of neoplastic cells positive). These included 5/10 (50%) somatotrophs, 7/17 (41%) lactotrophs, 2/5 (40%) mammosomatotrophs, 4/8 (50%) mixed somatotroph-lactotrophs, 3/5 (60%) PIT-1 positive plurihormonal tumours with TSH expression, 10/28 (36%) of PIT-1 positive plurihormonal tumours, and 4/10 (40%) of PIT-1 positive tumours with no hormonal expression. Only 2/32 (6%) transcription factor triple negative, hormone negative tumours, 5/113 (4%) of gonadotrophs, and 0/6 thyrotrophs or 0/30 corticotrophs showed significant staining. We conclude that PD-L1 expression is common in somatotrophs, lactotrophs, and PIT-1 positive plurihormonal PitNETs but rare in transcription factor negative, hormone negative PitNETs, gonadotrophs, and corticotrophs. If the therapeutic role of immunotherapy is to be explored in PitNETs, it may be that it is of most benefit in the PD-L1 high subgroup.
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References
Kloeppel G, Lloyd R, Osamura R, Roasi J (2017) Pathology and genetics of endocrine organs. 4th edn. Lyon: IARC Press.
Wang PF, Wang TJ, Yang YK, et al (2018) The expression profile of PD-L1 and CD8+ lymphocyte in pituitary adenomas indicating for immunotherapy. J Neurooncol 139(1):89-95.
Asa SL, Casar-Borota O, Chanson P, Delgrange E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N, Karavitaki N, Korbonits M, Laws ER Jr, Lopes MB, Maartens N, McCutcheon IE, Mete O, Nishioka H, Raverot G, Roncaroli F, Saeger W, Syro LV, Vasiljevic A, Villa C, Wierinckx A, Trouillas J; attendees of 14th Meeting of the International Pituitary Pathology Club, Annecy, France, November 2016 (2017) From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. Endocr Relat Cancer 24(4):C5-C8.
Molitch ME (2017) Diagnosis and Treatment of Pituitary Adenomas: A Review. JAMA 317(5):516-524.
Esposito D, Olsson DS, Ragnarsson O, Buchfelder M, Skoglund T, Johannsson G (2019) Non-functioning pituitary adenomas: indications for pituitary surgery and post-surgical management. Pituitary 22(4):422-434.
Freda PU, Beckers AM, Katznelson L, et al (2011) Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96(4):894-904.
Molitch ME (2009) Pituitary tumours: pituitary incidentalomas. Best Pract Res Clin Endocrinol Metab 23(5):667-675.
Fernandez-Balsells MM, Murad MH, Barwise A, Gallegos-Orozco JF, Paul A, Lane MA, Lampropulos JF, Natividad I, Perestelo-Perez L, Ponce de Leon-Lovaton PG, Erwin PJ, Carey J, Montori VM (2011) Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab 2011;96(4):905–912.
Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y (2003) A survey of pituitary incidentaloma in Japan. Eur J Endocrinol 149(2):123–127.
Karavitaki N, Collison K, Halliday J, Byrne JV, Price P, Cudlip S, Wass JA (2007) What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol 67(6):938–943.
Jordan J, Miller J, Cushing T, Seijo M, Batchelor T, Arrillaga-Romany I, Shih H, Nachtigall L, Loeffler J, Dietrich J (2018) Temozolomide therapy for aggressive functioning pituitary adenomas refractory to surgery and radiation: a case series. Neuro-Oncology Practice 5(1):64–68.
Loeffler JS, Shih HA (2011) Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 96(7):1992–2003.
Bruno OD, Juárez-Allen L, Christiansen SB, et al (2015) Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina. Int J Endocrinol 587893.
Ji Y, Vogel RI, Lou E (2016) Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neurooncol Pract 3(3):188-195.
Bush ZM, Longtine JA, Cunningham T, et al (2010) Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab 95(11):E280-90
Raverot G, Castinetti F, Jouanneau E, et al (2012) Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment. Clin Endocrinol (Oxf) 76(6):769-75
Bengtsson D, Schrøder HD, Andersen M, et al (2015) Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J Clin Endocrinol Metab 100(4):1689-98.
McCormack A, Dekkers OM, Petersenn S, et al (2018) Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol. 178(3):265-276.
Giuffrida G, Ferraù F, Laudicella R, Cotta OR, Messina E, Granata F, Angileri FF, Vento A, Alibrandi A, Baldari S, Cannavò S (2019) Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience. Endocr Connect 1;8(5):528–535.
Alshaikh OM, Asa SL, Mete O, Ezzat S (2019). An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors. Endocr Pathol. 30(2):118-127.
Manojlovic-Gacic E, Engström BE, Casar-Borota O (2018) Histopathological classification of non-functioning pituitary neuroendocrine tumors. Pituitary 21(2):119-129.
Tampourlou M, Ntali G, Ahmed S, et al (2017) Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers. J Clin Endocrinol Metab 102(6):1889-1897.
Dai C, Liu X, Ma W, Wang R (2019) The Treatment of Refractory Pituitary Adenomas. Front Endocrinol (Lausanne) 10:334.
Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nat Clin Pract Oncol 2(3):480–489
Marchetti A, Di Lorito A, Buttitta F (2017) Why anti-PD1/PDL1 therapy is so effective? Another piece in the puzzle. J Thorac Dis 9(12):4863-4866.
Gordon SR, Maute RL, Dulken BW, et al (2017) PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545(7655):495-499.
Kim H, Chung JH (2019) PD-L1 Testing in Non-small Cell Lung Cancer: Past, Present, and Future. J Pathol Transl Med 53(4):199-206.
Som A, Mandaliya R, Alsaadi D, et al (2019) Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases 7(4):405-418.
Trinh S, Le A, Gowani S, La-Beck NM (2019) Management of Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitor Therapy: a Minireview of Current Clinical Guidelines. Asia Pac J Oncol Nurs 6(2):154-160.
Mei Y, Bi WL, Greenwald NF, et al (2016) Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget 7(47):76565-76576.
Gill AJ, Toon CW, Clarkson A, et al (2014) Succinate dehydrogenase deficiency is rare in pituitary adenomas. Am J Surg Pathol 38(4):560-566.
Turchini J, Sioson L, Clarkson A, et al (2020) Utility of GATA-3 Expression in the Analysis of Pituitary Neuroendocrine Tumour (PitNET) Transcription Factors. Endocr Pathol 31:150–155.
Asa, S., Mete, O (2021) Cytokeratin profiles in pituitary neuroendocrine tumours. Human Pathology. 107: 87-95.
Majd N, Waguespack SG, Janku F, et al (2020) Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study. Journal for ImmunoTherapy of Cancer 8:e001532.
Lin AL, Jonsson P, Tabar V, Yang TJ, Cuaron J, Beal K, Cohen M, Postow M, Rosenblum M, Shia J, DeAngelis LM, Taylor BS, Young RJ, Geer EB (2018). Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab. J Clin Endocrinol Metab. 103(10):3925-3930.
Cooper WA, Russell PA, Cherian M, et al (2017) Intra- and Interobserver Reproducibility Assessment of PD-L1 Biomarker in Non-Small Cell Lung Cancer. Clin Cancer Res 23(16):4569-4577.
Brunnström H, Johansson A, Westbom-Fremer S, et al (2017) PD-L1 immunohistochemistry in clinical diagnostics of lung cancer: inter-pathologist variability is higher than assay variability. Mod Pathol 30(10):1411-1421.
Scognamiglio G, De Chiara A, Di Bonito M, Tatangelo F, Losito NS, Anniciello A, De Cecio R, D'Alterio C, Scala S, Cantile M, Botti G (2016) Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types. Int J Mol Sci 21;17(5):790.
O’Malley DP, Yang Y, Boisot S, et al (2019) Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases. Mod Pathol 32: 929–942.
Nishihara H, Soldati S, Mossu A, et al (2020) Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro. Fluids Barriers CNS 17, 3.
Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 33(12):579-89.
Albarel F, Castinetti F, and Brue, T (2019) MANAGEMENT OF ENDOCRINE DISEASE: Immune check point inhibitors-induced hypophysitis. European Journal of Endocrinology 181, 3, R107-R118.
Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE & Tolaney SM (2018) Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncology 4: 173–182.
Scott ES, Long GV, Guminski A, Clifton-Bligh RJ, Menzies AM & Tsang VH (2018) The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. European Journal of Endocrinology 178: 173–180.
Bellastella G, Maiorino MI, Bizzarro A, Giugliano D, Esposito K, Bellastella A & De Bellis A (2016) Revisitation of autoimmune hypophysitis: knowledge and uncertainties on pathophysiological and clinical aspects. Pituitary 19: 625–642.
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Turchini, J., Sioson, L., Clarkson, A. et al. PD-L1 Is Preferentially Expressed in PIT-1 Positive Pituitary Neuroendocrine Tumours. Endocr Pathol 32, 408–414 (2021). https://doi.org/10.1007/s12022-021-09673-2
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DOI: https://doi.org/10.1007/s12022-021-09673-2