Comparison of the predictive power of morphological and therapeutic stratification predictors of monohormonal somatotroph pituitary tumors in patients with acromegaly

Introduction. Given the heterogeneity of somatotroph tumors (STs), it is important to study diverse predictors of morphological identification and sensitivity to first-generation somatostatin receptor ligands (fg-SRLs).
Aim. Comparative analysis of the prognostic significance of predictors of STs pathomorphological status and the prospects for using fg-SRLs in patients with acromegaly.
Materials and methods. A retrospective analysis of the long-term efficacy of fg-SRLs was conducted in 634 patients with acromegaly. Treatment outcomes were compared with baseline clinical examination data, pharmacotherapeutic testing (PharmT) results (n = 496), cytological and immunohistochemical analysis data (n = 104), as well as quantitative indicators of relative tumor signal intensity (RTSI) on T2- and T1-weighted MRI (n = 106).
Results. Among the markers of morphological stratification of STs, the most informative are: age at diagnosis (AUC 0.686), tumor volume and maximum diameter (0.664 and 0.665), expression of the 2nd subtype of somatostatin receptors (SSTR2; 0.816), the difference and ratio of SSTR2 and SSTR5 (0.826 and 0.808), the proportion of cells with antibodies to GH (0.932) and with fibrous bodies (FB; 0.962), tumor cell composition (0.935), RTSI on T2-, T1- and (T2-T1)-weighted MRI (WI; 0.878, 0.822 and 0.918). Predictors of fg-SRLs efficacy include: volume and maximum diameter of STs (0.640 and 0.649), baseline IGF-1 index value (0.637), absolute and relative expression of SSTR2 (0.673, 0.688 and 0.713), proportion of cells with FB (0.698), tumor cell composition (0.742), results of RTSI on T2- and (T2-T1)-WI (0.684 and 0.636) and PharmT (%∆IGF-1 after 3–6 months – 0.840–0.849). The successful use of pegvisomant in patients refractory to fg-SRLs has been demonstrated.
Conclusions. Priority predictors of the morphofunctional status of STs and the long-term effectiveness of fg-SRLs simplifying the differential diagnosis of the relevant histotype and facilitating the management of acromegaly treatment have been identified.

1. Marrero-Rodríguez D, Moscona-Nissan A, Sidauy-Adissi J, HaidenbergDavid F, Jonguitud-Zumaya E, de Jesus Chávez-Vera L, et al. The molecular biology of sporadic acromegaly. Best Pract Res Clin Endocrinol Metab. 2024;38(3):101895. https://doi.org/10.1016/j.beem.2024.101895.

2. Guaraldi F, Ambrosi F, Ricci C, Di Sciascio L, Asioli S. Histopathology of growth hormone-secreting pituitary tumors: State of the art and new perspectives. Best Pract Res Clin Endocrinol Metab. 2024;38(3):101894. https://doi.org/10.1016/j.beem.2024.101894.

3. Gliga MC, Tătăranu LG, Popescu M, Chinezu L, Paşcanu MI. Immunohistochemical evaluation of biomarkers with predictive role in acromegaly: a literature review. Rom J Morphol Embryol. 2023;64(1):25–33. https://doi.org/10.47162/RJME.64.1.03.

4. Asa SL, Kucharczyk W, Ezzat S. Pituitary acromegaly: not one disease. Endocr Relat Cancer. 2017;24(3):C1–C4. https://doi.org/10.1530/ERC-16-0496.

5. Mete O, Wenig BM. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms. Head Neck Pathol. 2022;16(1):123–142. https://doi.org/10.1007/s12105-022-01435-8.

6. Wang L, He X, Lu L, Chen L, Peng C, Shao C, Ge R. Clinicopathological Analysis of Densely and Sparsely Granulated Somatotroph Tumors of Pituitary. World Neurosurg. 2024;185:e713–e720. https://doi.org/10.1016/j.wneu.2024.02.115.

7. Heng L, Liu X, Jia D, Guo W, Zhang S, Gao G et al. Preoperative prediction of granulation pattern subtypes in GH-secreting pituitary adenomas. Clin Endocrinol. 2021;95(1):134–142. https://doi.org/10.1111/cen.14465.

8. Rymuza J, Zhang Q, Bujko M. PIT-1/SF-1-positive pituitary tumors in patients with acromegaly: transcriptomic perspective. Acta Neuropathol Commun. 2025;13(1):174. https://doi.org/10.1186/s40478-025-02091-z.

9. Dottermusch M, Ryba A, Ricklefs FL, Flitsch J, Schmid S, Glatzel M et al. Pituitary neuroendocrine tumors with PIT1/SF1 co-expression show distinct clinicopathological and molecular features. Acta Neuropathol. 2024;147(1):16. https://doi.org/10.1007/s00401-024-02686-1.

10. Mayr B, Buslei R, Theodoropoulou M, Stalla GK, Buchfelder M, Schöfl C. Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas. Eur J Endocrinol. 2013;169(4):391–400. https://doi.org/10.1530/EJE-13-0134.

11. Gadelha MR, Kasuki L, Lim DST, Fleseriu M. Systemic Complications of Acromegaly and the Impact of the Current Treatment Landscape: An Update. Endocr Rev. 2019;40(1):268–332. https://doi.org/10.1210/er.2018-00115.

12. Maroufi SF, Assar M, Khorasanizadeh M, Sabet FM, Sabahi M, Dabecco R et al. Assessment of multimodal treatment options in recurrent and persistent acromegaly: a systematic review and meta-analysis. J Neurooncol. 2024;168(1):13–25. https://doi.org/10.1007/s11060-024-04658-7.

13. Puig-Domingo M, Marazuela M. Precision medicine in the treatment of acromegaly. Minerva Endocrinol. 2019;44(2):169–175. https://doi.org/10.23736/S0391-1977.18.02937-1.

14. Kasuki L, Lamback E, Antunes X, Gadelha MR. Biomarkers of response to treatment in acromegaly. Expert Rev Endocrinol Metab. 2024;19(1):71–80. https://doi.org/10.1080/17446651.2023.2293107.

15. Ilie MD, Tabarin A, Vasiljevic A, Bonneville JF, Moreau-Grangé L, Schillo F et al. Predictive Factors of Somatostatin Receptor Ligand Response in Acromegaly-A Prospective Study. J Clin Endocrinol Metab. 2022;107(11):2982–2991. https://doi.org/10.1210/clinem/dgac512.

16. Asaad W, Pachuashvili NV, Urusova LS, Bondarenko EV, Lapshina AM, Utkina MV et al. The role of immunohistochemical analysis in improving the diagnosis accuracy of neuroendocrine tumors of the pituitary gland. Endocrine Surgery. 2025;19(1):13–22. (In Russ.) https://doi.org/10.14341/serg13007.

17. Potorac I, Beckers A, Bonneville JF. T2-weighted MRI signal intensity as a predictor of hormonal and tumoral responses to somatostatin receptor ligands in acromegaly: a perspective. Pituitary. 2017;20(1):116–120. https://doi.org/10.1007/s11102-017-0788-8.

18. Antsiferov MB, Petraikin AV, Alexeeva TM, Pronin EV, Khoruzhaya AN, Tamaeva SM. Modern possibilities of tumor-oriented diagnosis and treatment for acromegaly. Farmateka. 2023;(3):78–88. (In Russ.) https://doi.org/10.18565/pharmateca.2023.3.78-88.

19. Petersenn S, Houchard A, Sert C, Caron PJ; PRIMARYS Study Group. Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study. Pituitary. 2020;23(2):171–181. https://doi.org/10.1007/s11102-019-01020-3.

20. Antsiferov MB, Alekseeva TM, Pronin EV, Pronin VS. Predictors of acromegaly clinical history and treatment effectiveness (based on Moscow Register Data). Endocrinology: News, Opinions, Training. 2020;9(3):26–38. (In Russ.) https://doi.org/10.33029/2304-9529-2020-9-3-26-38.

21. Nista F, Corica G, Castelletti L, Khorrami K, Campana C, Cocchiara F et al. Clinical and Radiological Predictors of Biochemical Response to First-Line Treatment With Somatostatin Receptor Ligands in Acromegaly: A Real-Life Perspective. Front Endocrinol. 2021;12:677919. https://doi.org/10.3389/fendo.2021.677919.

22. Godlewska-Nowak M, Grochowska A, Zieliński G, Bogusławska A, Adamek D, Maksymowicz M et al. Quantitative and qualitative assessment of a pituitary neuroendocrine tumor’s T2-signal intensity in acromegaly – a call for unification. Front Endocrinol. 2024;15:1441745. https://doi.org/10.3389/fendo.2024.1441745.

23. Pronin EV, Pronin VS, Antsiferov MB, Petraikin AV, Alexeeva TM, Lapshina AM et al. Predictors of morphofunctional features of somatotrophic tumors and of the effectiveness of treatment with first-generation somatostatin receptor ligands. Meditsinskiy Sovet. 2024;(6):98–111. (In Russ.) https://doi.org/10.21518/ms2024-147.

24. Gatto F, Feelders RA, van der Pas R, Kros JM, Waaijers M, Sprij-Mooij D et al. Immunoreactivity score using an anti-sst2A receptor monoclonal antibody strongly predicts the biochemical response to adjuvant treatment with somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2013;98(1):E66–E71. https://doi.org/10.1210/jc.2012-2609.

25. Obari A, Sano T, Ohyama K, Kudo E, Qian ZR, Yoneda A et al. Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol. 2008;19(2):82–91. https://doi.org/10.1007/s12022-008-9029-z.

26. Liu CX, Wang SZ, Heng LJ, Han Y, Ma YH, Yan LF et al. Predicting Subtype of Growth Hormone Pituitary Adenoma based on Magnetic Resonance Imaging Characteristics. J Comput Assist Tomogr. 2022;46(1):124–130. https://doi.org/10.1097/RCT.0000000000001249.

27. Wu N, Wu N, Wang N, Zhu Y. Progress in the pathogenesis and treatment of pituitary neuroendocrine tumors (PitNETs): From molecular mechanisms to emerging therapies. Mol Cell Probes. 2025;83:102039. https://doi.org/10.1016/j.mcp.2025.102039.

28. Przhiyalkovskaya EG, Mokrysheva NG, Troshina EA, Melnichenko GA, Dedov II, Antsiferov MB et al. Guidelines on diagnostics and treatment of acromegaly (draft). Obesity and Metabolism. 2024;21(2):215–249. (In Russ.) https://doi.org/10.14341/omet13153.

29. Melmed S, di Filippo L, Fleseriu M, Mercado M, Karavitaki N, Gurnell M et al. Consensus on acromegaly therapeutic outcomes: an update. Nat Rev Endocrinol. 2025;21:718–737. https://doi.org/10.1038/s41574-025-01148-2.

30. Coopmans EC, Korevaar TIM, van Meyel SWF, Daly AF, Chanson P, Brue T et al. Multivariable Prediction Model for Biochemical Response to FirstGeneration Somatostatin Receptor Ligands in Acromegaly. J Clin Endocrinol Metab. 2020;105(9):dgaa387. https://doi.org/10.1210/clinem/dgaa387.

31. Biagetti B, Iglesias P, Villar-Taibo R, Moure MD, Paja M, Araujo-Castro M et al. Factors associated with therapeutic response in acromegaly diagnosed in the elderly in Spain. Front Endocrinol. 2022;13:984877. https://doi.org/10.3389/fendo.2022.984877.

32. Gliga MC, Chinezu L, Pascanu IM. Predicting Response to Medical Treatment in Acromegaly via Granulation Pattern, Expression of Somatostatin Receptors Type 2 and 5 and E-Cadherin. Int J Mol Sci. 2024;25(16):8663. https://doi.org/10.3390/ijms25168663.

33. Durmuş ET, Atmaca A, Kefeli M, Çalışkan S, Mete O, Aslan K et al. Age, GH/IGF-1 levels, tumor volume, T2 hypointensity, and tumor subtype rather than proliferation and invasion are all reliable predictors of biochemical response to somatostatin analogue therapy in patients with acromegaly: A clinicopathological study. Growth Horm IGF Res. 2022;67:101502. https://doi.org/10.1016/j.ghir.2022.101502.

34. Del Corso LM, Mesa Junior CO, Andrade VFC, Fidalski SZK, Boguszewski CL. Diagnostic, therapeutic, and prognostic characteristics of patients with acromegaly according to tumor size at diagnosis. Pituitary. 2024;27(5):537–544. https://doi.org/10.1007/s11102-024-01432-w.

35. Shen M, Yang Y, He W, Qiao N, He M, Shou X et al. Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: A hospital-based study of 237 cases. Growth Horm IGF Res. 2020;55:101354. https://doi.org/10.1016/j.ghir.2020.101354.

36. Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T et al. Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J Clin Endocrinol Metab. 2013;98(11):E1730–E1739. https://doi.org/10.1210/jc.2013-2145.

37. Berton AM, Prencipe N, Bertero L, Baldi M, Bima C, Corsico M et al. Resistance to Somatostatin Analogs in Italian Acromegaly Patients: The MISS Study. J Clin Med. 2022;12(1):25. https://doi.org/10.3390/jcm12010025.

38. Heck A, Emblem KE, Casar-Borota O, Bollerslev J, Ringstad G. Quantitative analyses of T2-weighted MRI as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly. Endocrine. 2016;52(2):333–343. https://doi.org/10.1007/s12020-015-0766-8.

39. Luo M, Yu J, Tang R. Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly. J Neurooncol. 2024;167(3):415–425. https://doi.org/10.1007/s11060-024-04620-7.

40. Marques-Pamies M, Gil J, Jordà M, Puig-Domingo M. Predictors of Response to Treatment with First-Generation Somatostatin Receptor Ligands in Patients with Acromegaly. Arch Med Res. 2023;54(8):102924. https://doi.org/10.1016/j.arcmed.2023.102924.

41. Marazuela M, Martínez-Hernandez R, Marques-Pamies M, Biagetti B, Araujo-Castro M, Puig-Domingo M. Predictors of biochemical response to somatostatin receptor ligands in acromegaly. Best Pract Res Clin Endocrinol Metab. 2024;38(4):101893. https://doi.org/10.1016/j.beem.2024.101893.

42. Lim DST, Fleseriu M. Personalized Medical Treatment of Patients With Acromegaly: A Review. Endocr Pract. 2022;28(3):321–332. https://doi.org/10.1016/j.eprac.2021.12.017.

43. Araujo-Castro M, Biagetti B, Menéndez Torre E, Novoa-Testa I, Cordido F, Pascual-Corrales E et al. Pegvisomant and pasireotide in PRL and GH cosecreting vs GH-secreting Pit-NETs. Endocr Relat Cancer. 2024;31(7):e240043. https://doi.org/10.1530/ERC-24-0043.