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Akbar S oltani . MD . MSc.Endocrinologist Evidence Based Medicine Research Center

Non functioning pituitary adenomas, non-functioning pituitary neuroendocrine tumores (NF- PitNETS ) Clinical cases. Akbar S oltani . MD . MSc.Endocrinologist Evidence Based Medicine Research Center Critical Thinking Group Tehran University of Medical Sciences www.ebm.ir.

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Akbar S oltani . MD . MSc.Endocrinologist Evidence Based Medicine Research Center

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  1. Non functioning pituitary adenomas,non-functioning pituitary neuroendocrine tumores (NF-PitNETS)Clinical cases Akbar Soltani. MD.MSc.Endocrinologist Evidence Based Medicine Research Center Critical Thinking Group Tehran University of Medical Sciences www.ebm.ir

  2. 1st case: Mrs B., 55 yo •Previous history –Mammary benign cyst –Bilateral ovariectomy when 48yo, HRT for menopause –Hysterectomy when 49yo (endometriosis) •Recent history: –Consults an endocrinologist for weight gain, –He measures PRL level which is increased to 120 ng/ml (N<20) •Normal clinical examination

  3. MrsB., 55 yo MRI macroadenoma measuring 28X25X20 mm with suprasellar expansion suprasellaire compressing the optic chiasm The qualitative importance of T2 for NFPA vs. FUNCTIONAL?

  4. Hardy’s classification of pituitary tumors: classification of sphenoid bone invasion • grade 0: intact with normal contour; • Grade I: intact with bulging floor • grade II: intact, with enlarged fossa • grade III: localized sellardestruction • grade IV: diffuse destruction Neuroendocrinology 2015;101:87–104

  5. Hardy’s classification of pituitary tumors: classification of the suprasellar extension • grade A: suprasellarcistern only • grade B: recess of the third ventricle • grade C: whole anterior third ventricle • grade D: intracranial extradural • grade E extracranialextradural (cavernous sinus) Neuroendocrinology 2015;101:87–104

  6. Knosp’s classification of cavernous sinus invasion Neuroendocrinology 2015;101:87–104

  7. Mrs B., 55 yo

  8. Q1: Which hormonal work up do you plan for this patient? • 1.Basal FSH, LH, alpha-subunit • 2.TRH-test • 3.ACTH-stimulation test • 4.GnRH-test • 5.Basal fT4, fT3, TSH

  9. MrsB., 55 yoHormonal evaluation • Insulin tolerance test –Peak cortisol: 23 μg/dl –Peak GH: 5 μg/l • fT4: 11 pmol/l (N 9-18) ; TSH : 2.6 mIU/L • FSH: 23 IU/L, LH: 2.8 IU/L, • Free alpha subunit: 1.5 IU/L • Cortisol after 1mg overnight DEX suppr. test : 0.2 μg/dl • IGF-I: 45 ng/ml (N 150-220) • PRL : 114 ng/ml (with dilution)

  10. TRH test Gonadotroph adenoma: increase in of LHβ-subunit, and less often intact FSH and LH. Normal: no response of intact FSH and FSHβ, and no more than a 33% increase N Engl J Med 1991;324(9):58994 J ClinEndocrinolMetab 1993;77:13525.

  11. MrsB., 55 yo Diagnosis •Pituitary macroadenoma •Moderate hyperprolactinemia suggestive of stalk interruption •No thyrotropicdeficiency, no corticotropicdeficiency •GH deficiency •Increased FSH levels…but low LH levels in a post-menopausal woman •(No evidence for a « silent » corticotropic adenoma) Likely gonadotropic adenoma (secreting FSH and free alpha-subunit)

  12. Distribution of pituitary adenomas subtypes Prevalence of NFPA : 13 to 25 per 100 000 inhabitants Fernandez et al. Clin Endocrinol 2010

  13. MrsB., 55 yoTreatment •Transsphenoidalremoval of the macroadenoma(considered as complete by the neurosurgeon) •Histology : adenoma with few cytological signs of secretion •Immunocytochemistry : –Positivity for anti alphaSU: <5% of cells –Positivity for anti ß-LH: <5% of cells –Positivity for anti ß-FSH: 50 à 75% of cells Gonadotropic adenoma

  14. BARRIERS TO OPTIMAL PRACTICE Lack of validated model fro prediction of natural and clinical history low molecular weight cytokeratin (LMWCK) [ O-6-methylguanine-DNA methyltransferase (MGMT) Trouillas J, et al.ActaNeuropathol.2013;126:123-135

  15. Trouillas J, et al.ActaNeuropathol.2013;126:123-135

  16. BARRIERS TO OPTIMAL PRACTICE Lack of validated pathology reporting

  17. Outcomes of surgery Remnant No remnant

  18. Outcomes of surgery Meta-analysis of 31 studies (5022 patients) for NFPA, Roelfsemaet al. Pituitary 2012

  19. MrsB., 55 yoPostoperative (3 months) evaluation •Normalization of PRL levels •Thyrotropic and corticotropic functions remain normal; GHD persists •FSH: 5 IU/L •LH: 1,9 IU/L • alpha SU : 0.39 U/L

  20. Incidence of new hypopituitarism after surgery for NFPA Surgery provided recovery of normal anterior pituitary function in ; 30% of cases, at a mean 1 year’s follow-up The risk of postoperative deterioration in pituitary function is; 10% Roelfsemaet al. Pituitary 2012

  21. MrsB., 55 yoPostoperative MRI Normalization of visual fields and visual acuity

  22. Q: At this point, what is your attitude in this patient without remnant? 1.Surveillance (watch and see) 2.Systematic adjuvant fractionated radiotherapy 3.Systematic adjuvant gamma-knife

  23. MrsB., 55 yoDecision of simple surveillance Long term follow up : no recurrence

  24. 2nd case: Mr T., 30 yo •Recent history –Headaches, sight •Ophtalmologiceval.: –AV LE 4/10; RE 10/10 –VF: BT hemianopsia •MRI

  25. MrT., 30 yo •Transsphenoidal surgery : incomplete removal of the pituitary adenoma •Immunocytochemistry: FSHß +, Ki67+ (2%), p53- •Oph. evaluation after 1 mth: –AV 10/10 (both eyes) –Improvement in VF •MRI at 6 months postop. Decision of follow up…

  26. BARRIERS TO OPTIMAL PRACTICENonavailability of genetic testing • Up to 5% of PA are familial adenomas • Familial Isolated Pituitary Adenomas (FIPA): • Germlinemutations in aryl hydrocarbon receptor-interacting protein (AIP) gene in 20% of FIPA (nonfunctioning tumor is rare) • MEN -1 and MEN-4 • Screening for both AIP and MEN-1 mutations needs to be considered in patients diagnosed with pituitary adenoma under the age of 21 years • Of clinical importance is that adenomas in patients with MEN1 or AIP mutations are big, invasive, and may not respond well to standard medical therapy. Vierimaa O, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science (New York,NY). 2006;312(5777):1228-1230.

  27. Outcomes of surgery MRI at 1 year MRI at 3 year

  28. Q: At this point, what is your attitude in this patient with a remnant which increases ? 1.Pursue visual and MRI surveillancce 2.Fractionated radiotherapy 3.Repeat surgery and then surveillance (avoid radiotherapy) 4.Repeat surgery for decreasing the volume and propose gamma-knife 5.Treatment with cabergoline

  29. Outcomes of surgery Predictive factors of regrowth: • Ki67 • Genetic • Young age ? • ……. 2b: OR=7.5 MRI at 1 year MRI at 3 year Surgical revision for remnant: • Complete resection? • Symptomatic (optic chiasm) • Regrowth after radiation • …

  30. Growth of the remnant: 47 (47%) of 100 patients Recurrence: 10 (24%) of 42 patients

  31. NFPA relapse percentages after surgery in the literature

  32. Time course of NFPA recurrences after surgery Meta-analysis of 31 studies (5022 patients) for NFPA Roelfsemaet al. Pituitary 2012

  33. What are the predictors of risk of NFPA relapse ? Risk of growth of the remnant ? Remnant Risk of recurrence ? No remnant

  34. Management of relapsing NFPA 1- Conservative management •In the absence of remnant, the risk of recurrence after surgery is 12%, mainly between 5 and 15 years… MRI surveillance +++ •In the presence of a remnant (e.g. in the cavernous sinus), the risk of regrowth is 44% at 5 years and 60% at 10 years… MRI surveillance possible. But at which frequency? Roelfsemaet al. Pituitary 2012

  35. MrT., 52 yo« Watch and see » MRI at 3 year MRI at 1 year What to do?

  36. BARRIERS TO OPTIMAL PRACTICE Different growth patterns of PAs • Follow up of 15 NFPA postop • remnants (7.4 yrs) • Growth is exponential (n=9) • or logistic (n=5) not linear Honneger et al. Eur J Endocrinol 2008

  37. Assuming that the tumor had a form of an ellipsoid, the increase in volume was calculated to be 28.5% over the 5 years, giving a TVDT of 14.5 years, if the tumor growth continued to be exponential. • Median tumor volume doubling time 3.1 years (range: 0.8–27.2 years)

  38. The natural course of tumor volume in clinically nonfunctioning pituitary macroadenomas • growth will be observed in 50% during 5 yr • In 34 of the 304 (11%) patients spontaneous regression • of tumor volume occurred during long-term follow-up (apoplexy?) J ClinEndocrinolMetab, October 2008, 93(10):3717–3726

  39. BARRIERS TO OPTIMAL PRACTICE Follow-Up Strategy • MRI • In a series of nonoperatedpatients • mean increase in diameter : 0.6 mm/yr • below the detection limit of currently used MRIs • Moreover, it is important to compare sequential MRIs with the firstpostoperative MRI • Visual assessment • low negative predictive valuefor recurrence • especially : with large distance between pituitary tumor and optic chiasm.

  40. Management of relapsing NFPA 2- Postoperative radiotherapy It works!

  41. Radiotherapy decreases the risk of NFPA relapse Cox multivariate analysis

  42. Radiotherapy decreases the risk of NFPA relapse Usually, a stable or decreased tumor volume is observed in .90% of cases. Tampourlou et al. recently reported that there was a 12.5% risk of further regrowth of NFPAs in patients treated by surgery and first radiotherapy. J Clin Endocrinol Metab. 2017;102(6): 1889–1897.

  43. Radiosurgery Control of tumor growth (stabilization or decrease) achieved in 95 to 100% of patients after 7 years (15 studies)

  44. Side-effects of radiotherapy Hypopituitarism –Well-known after fractionated RT… –After gammaknife : new pituitary deficiencies in 8-10% after 2-3 years and 32-42% after 5 years Increased risk of CVA Increased risk of second tumor Optic neuropathy Temporal lobe necrosis Brada et al. 2002; Tomlinson et al. 2001; Tsang et al. 1993; Minitti et al. 2005; Loeefler et al. 2011; Pereira et al. 2012

  45. Conclusion : A proposal for strategy after surgery in NFPAs

  46. Management of relapsing NFPA 2- Medical treatment ? • GnRH analogues : no antitumoral effects and risk of pituitary apoplexy ! Liuzziet al. 1991; Boute et al. 1991; Colombo et al. 1994; Ando et al. 1995; Chanson et al. 1995; Morsi et al. 1996; Schuval et al. 1996; Chanson et al. 1997

  47. Somatostatin analogs and NFPAs (1) •Somatostatin receptors present on cell membranes •Expression of sst1, 2 , 3 and 5 Nielsen et al. 2001; Florio et al. 1999; Oppizzi et al. 1998; Borson-Chazot et al. 1997; Plockinger et al. 1997; Saveanu et al. 2001; Zatelli et al. 2004

  48. Somatostatin analogs and NFPAs (2) •Effects of octreotide on visual fields… –8 patients –Results: •Improvement: 6/8; normalized : 3, •Rapid effect (4-6h in 2 pts), •Sustained (12 months) Warnetet al. J Neurosurg 1989

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