Abstract
Introduction
Histologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH—releasing hormone secreting tumors or in familial pituitary tumor syndromes.
Materials and methods
A literature search was performed for information regarding pathology, GH-producing tumors and acromegaly.
Results
This review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary.
Conclusion
The importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.
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References
Melmed S (2006) Medical progress: acromegaly. N Engl J Med 355(24):2558–2573. doi:10.1056/NEJMra062453
Melmed S (2016) Pituitary medicine from discovery to patient-focused outcomes. J Clin Endocrinol Metab 101(3):769–777. doi:10.1210/jc.2015-3653
Lopes MBS (2010) Growth hormone-secreting adenomas: pathology and cell biology. Neurosurg Focus 29(4):E2. doi:10.3171/2010.7.FOCUS10169
Osamura RY, Kajiya H, Takei M, Egashira N, Tobita M, Takekoshi S, Teramoto A (2008) Pathology of the human pituitary adenomas. Histochem Cell Biol 130(3):495–507. doi:10.1007/s00418-008-0472-1
Kiseljak-Vassiliades K, Shafi S, Kerr JM, Phang TL, Kleinschmidt-DeMasters BK, Wierman ME (2012) Clinical implications of growth hormone-secreting tumor subtypes. Endocrine 42(1):18–28. doi:10.1007/s12020-012-9660-9
Mete O, Asa SL (2013) Therapeutic implications of accurate classification of pituitary adenomas. Semin Diagn Pathol 30(3):158–164. doi:10.1053/j.semdp.2013.06.002
Horvath E, Kovacs K (2006) Pathology of acromegaly. Neuroendocrinology 83(3–4):161–165. doi:10.1159/000095524
Kiseljak-Vassiliades K, Carlson N, Borges M, Kleinschmidt-DeMasters BK, Lillehei K, Kerr J, Wierman M (2014) Growth hormone tumor histological subtypes predict response to surgical and medical therapy. Endocrine. doi:10.1007/s12020-014-0383-y
Saeger W, Honegger J, Theodoropoulou M, Knappe UJ, Schofl C, Petersenn S, Buslei R (2016) Clinical impact of the current WHO classification of pituitary adenomas. Endocr Pathol. doi:10.1007/s12022-016-9418-7
Puig DM (2015) Treatment of acromegaly in the era of personalized and predictive medicine. Clin Endocrinol. doi:10.1111/cen.12731
Cuevas-Ramos D, Carmichael JD, Cooper O, Bonert VS, Gertych A, Mamelak AN, Melmed SA (2014) Structural and functional acromegaly classification. J Clin Endocrinol Metab. doi:10.1210/jc.2014-2468
Syro LV, Rotondo F, Ramirez A, Di Ieva A, Sav MA, Restrepo LM, Serna CA, Kovacs K (2015) Progress in the diagnosis and classification of pituitary adenomas. Front Endocrinol (Lausanne) 6:97. doi:10.3389/fendo.2015.00097
Gomez-Hernandez K, Ezzat S, Asa SL, Mete O (2015) Clinical implications of accurate subtyping of pituitary adenomas: perspectives from the treating physician. Turk Patoloji Derg 31(Suppl 1):4–17. doi:10.5146/tjpath.2015.01311
Sano T, Ohshima T, Yamada S (1991) Expression of glycoprotein hormones and intracytoplasmic distribution of cytokeratin in growth hormone-producing pituitary adenomas. Pathol Res Pract 187(5):530–533. doi:10.1016/s0344-0338(11)80135-4
Obari A, Sano T, Ohyama K, Kudo E, Qian ZR, Yoneda A, Rayhan N, Rahman MM, Yamada S (2008) Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol 19(2):82–91. doi:10.1007/s12022-008-9029-z
Yamada S, Aiba T, Sano T, Kovacs K, Shishiba Y, Sawano S, Takada K (1993) Growth hormone-producing pituitary adenomas: correlations between clinical characteristics and morphology. Neurosurgery 33(1):20–27
Mori R, Inoshita N, Takahashi-Fujigasaki J, Joki T, Nishioka H, Abe T, Fujii T, Yamada S (2013) Clinicopathological features of growth hormone-producing pituitary adenomas in 242 acromegaly patients: classification according to hormone production and cytokeratin distribution. ISRN Endocrinol 2013:723432. doi:10.1155/2013/723432
Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J (2009) Pituitary tumours: acromegaly. Best Pract Res Clin Endocrinol Metab 23(5):555–574. doi:10.1016/j.beem.2009.05.010
Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S (2007) Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol 156(2):203–216. doi:10.1530/eje.1.02326
Xu B, Sano T, Yoshimoto K, Yamada S (2002) Downregulation of E-cadherin and its undercoat proteins in pituitary growth hormone cell adenomas with prominent fibrous bodies. Endocr Pathol 13(4):341–351
Nishioka H, Haraoka J, Akada K (2003) Fibrous bodies are associated with lower GH production and decreased expression of E-cadherin in GH-producing pituitary adenomas. Clin Endocrinol 59(6):768–772. doi:10.1046/j.1365-2265.2003.01921.x
Sano T, Rong QZ, Kagawa N, Yamada S (2004) Down-regulation of E-cadherin and catenins in human pituitary growth hormone-producing adenomas. Front Horm Res 32:127–132
Fougner SL, Lekva T, Borota OC, Hald JK, Bollerslev J, Berg JP (2010) The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. J Clin Endocrinol Metab 95(5):2334–2342. doi:10.1210/jc.2009-2197
Zhou K, Jin H, Luo Y (2013) Expression and significance of E-cadherin and beta-catenins in pituitary adenoma. Int J Surg Pathol 21(4):363–367. doi:10.1177/1066896912471850
Mete O, Asa SL (2012) Clinicopathological correlations in pituitary adenomas. Brain Pathol 22(4):443–453. doi:10.1111/j.1750-3639.2012.00599.x
Vidal S, Syro L, Horvath E, Uribe H, Kovacs K (1999) Ultrastructural and immunoelectron microscopic study of three unusual plurihormonal pituitary adenomas. Ultrastruct Pathol 23(3):141–148
Erickson D, Scheithauer B, Atkinson J, Horvath E, Kovacs K, Lloyd RV, Young WF Jr (2009) Silent subtype 3 pituitary adenoma: a clinicopathologic analysis of the Mayo Clinic experience. Clin Endocrinol 71(1):92–99. doi:10.1111/j.1365-2265.2008.03514.x
Mete O, Gomez-Hernandez K, Kucharczyk W, Ridout R, Zadeh G, Gentili F, Ezzat S, Asa SL (2016) Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas. Mod Pathol Off J U S Can Academy of Pathol Inc 29(2):131–142. doi:10.1038/modpathol.2015.151
Garby L, Caron P, Claustrat F, Chanson P, Tabarin A, Rohmer V, Arnault G, Bonnet F, Chabre O, Christin-Maitre S, du-Boullay H, Murat A, Nakib I, Sadoul JL, Sassolas G, Claustrat B, Raverot G, Borson-Chazot F, GTE (2012) Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH): a French nationwide series of 21 cases. J Clin Endocrinol Metab 97(6):2093–2104. doi:10.1210/jc.2011-2930
Trouillas J, Labat-Moleur F, Sturm N, Kujas M, Heymann MF, Figarella-Branger D, Patey M, Mazucca M, Decullier E, Verges B, Chabre O, Calender A (2008) Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol 32(4):534–543. doi:10.1097/PAS.0b013e31815ade45
Salenave S, Boyce AM, Collins MT, Chanson P (2014) Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab 99(6):1955–1969. doi:10.1210/jc.2013-3826
Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernandez-Ramirez LC, Kapur S, Caimari F, Evanson J, Ferrau F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramirez-Renteria C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, Korbonits M (2016) Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta neuropathologica communications 4(1):56. doi:10.1186/s40478-016-0328-1
Schernthaner-Reiter MH, Trivellin G, Stratakis CA (2016) MEN1, MEN4, and Carney Complex: pathology and Molecular Genetics. Neuroendocrinology 103(1):18–31. doi:10.1159/000371819
Chinezu L, Jouanneau E, Vasiljevic A, Trouillas J, Raverot G (2013) Silent GH pituitary tumor: diagnostic and therapeutic challenges. Ann Endocrinol 74(5–6):491–495. doi:10.1016/j.ando.2013.09.003
Cooper O, Melmed S (2012) Subclinical hyperfunctioning pituitary adenomas: the silent tumors. Best Pract Res Clin Endocrinol Metab 26(4):447–460. doi:10.1016/j.beem.2012.01.002
Mayson SE, Snyder PJ (2014) Silent (clinically nonfunctioning) pituitary adenomas. J Neurooncol 117(3):429–436. doi:10.1007/s11060-014-1425-2
Mohammed S, Syro L, Abad V, Salehi F, Horvath E, Scheithauer BW, Kovacs K, Cusimano M (2009) Silent somatotroph adenoma of the pituitary in an adolescent. Can J Neurol Sci 36(1):123–125
Sav A, Syro LV, Scheithauer BW, Rotondo F, Builes CA, Horvath E, Kovacs K (2012) Silent somatotroph adenoma: a morphologic, immunohistochemical and electron microscopic study: a case report. J Med Cases. doi:10.4021/jmc416w
Vieira Neto L, Chimelli L, Pereira PJ, Gasparetto EL, Bines J, Wildemberg LE, Gadelha MR (2013) The role of temozolomide in the treatment of a patient with a pure silent pituitary somatotroph carcinoma. Endocr Pract: Off J Am Coll Endocrinol Am Assoc Clin Endocrinol 19(6):e145–149. doi:10.4158/ep12400.cr
Lloyd RV, Kovacs K, Young WF Jr, Farrell W, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW, Hern E (2004) Pituitary tumors: introduction. In: DeLlelis RA, Lloyd RV, Heitz PU, Eng C (eds) Pathology and Genetics of Tumours of Endocrine Organs. IARC press, Lyon, pp 10–13
Trouillas J, Roy P, Sturm N, Dantony E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C, Brue T, Cornelius A, Dufour H, Jouanneau E, Francois P, Galland F, Mougel F, Chapuis F, Villeneuve L, Maurage CA, Figarella-Branger D, Raverot G, Barlier A, Bernier M, Bonnet F, Borson-Chazot F, Brassier G, Caulet-Maugendre S, Chabre O, Chanson P, Cottier JF, Delemer B, Delgrange E, Di Tommaso L, Eimer S, Gaillard S, Jan M, Girard JJ, Lapras V, Loiseau H, Passagia JG, Patey M, Penfornis A, Poirier JY, Perrin G, Tabarin A (2013) A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol 126(1):123–135. doi:10.1007/s00401-013-1084-y
Heaney AP (2011) Pituitary Carcinoma: difficult Diagnosis and Treatment. J Clin Endocrinol Metabol 96(12):3649–3660. doi:10.1210/jc.2011-2031
Heaney A (2014) Management of aggressive pituitary adenomas and pituitary carcinomas. J Neurooncol 117(3):459–468. doi:10.1007/s11060-014-1413-6
Bengtsson D, Schroder HD, Andersen M, Maiter D, Berinder K, Rasmussen UF, Rasmussen AK, Johannsson G, Hoybye C, van der Lely AJ, Petersson M, Ragnarsson O, Burman P (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):1689–1698. doi:10.1210/jc.2014-4350
Lehr H-A, Folpe A, Yaziji H, Kommoss F, Gown AM (2000) Cytokeratin 8 immunostaining pattern and E-cadherinexpression distinguish lobular from ductal breast carcinoma. Am J Clin Pathol 114(2):190–196. doi:10.1309/cpux-kweh-7b26-ye19
Asa SL, Digiovanni R, Jiang J, Ward ML, Loesch K, Yamada S, Sano T, Yoshimoto K, Frank SJ, Ezzat S (2007) A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors. Cancer Res 67(15):7505–7511. doi:10.1158/0008-5472.can-07-0219
Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J (2012) Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol 76(1):96–102. doi:10.1111/j.1365-2265.2011.04163.x
Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M (2013) Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary 16(4):490–498. doi:10.1007/s11102-012-0445-1
Mayr B, Buslei R, Theodoropoulou M, Stalla GK, Buchfelder M, Schöfl C (2013) Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas. Eur J Endocrinol 169(4):391–400. doi:10.1530/eje-13-0134
Ballman KV (2015) Biomarker: predictive or Prognostic? J Clin Oncol: Off J Am Soc Clin Oncol 33(33):3968–3971. doi:10.1200/jco.2015.63.3651
Nalejska E, Maczynska E, Lewandowska MA (2014) Prognostic and predictive biomarkers: tools in personalized oncology. Mol Diagn Ther 18(3):273–284. doi:10.1007/s40291-013-0077-9
Syro LV, Rotondo F, Kovacs K (2015) Biomarkers of acromegaly. Endocrine 49(1):4–5. doi:10.1007/s12020-015-0579-9
Bhayana S, Booth GL, Asa SL, Kovacs K, Ezzat S (2005) The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab 90(11):6290–6295. doi:10.1210/jc.2005-0998
Taboada GF, Luque RM, Neto LV, de Machado OE, Sbaffi BC, Domingues RC, Marcondes JB, Chimelli LM, Fontes R, Niemeyer P, de Carvalho DP, Kineman RD, Gadelha MR (2008) Quantitative analysis of somatostatin receptor subtypes (1-5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur J Endocrinol 158(3):295–303. doi:10.1530/eje-07-0562
Colao A, Auriemma RS, Lombardi G, Pivonello R (2011) Resistance to somatostatin analogs in acromegaly. Endocr Rev 32(2):247–271. doi:10.1210/er.2010-0002
Chinezu L, Vasiljevic A, Jouanneau E, Francois P, Borda A, Trouillas J, Raverot G (2014) Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies. Hum Pathol 45(1):71–77. doi:10.1016/j.humpath.2013.08.007
Kiseljak-Vassiliades K, Xu M, Mills TS, Smith EE, Silveira LJ, Lillehei KO, Kerr JM, Kleinschmidt-DeMasters BK, Wierman ME (2015) Differential somatostatin receptor (SSTR) 1–5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors. Mol Cell Endocrinol 417:73–83. doi:10.1016/j.mce.2015.09.016
Gatto F, Biermasz NR, Feelders RA, Kros JM, Dogan F, van der Lely AJ, Neggers SJ, Lamberts SW, Pereira AM, Ferone D, Hofland LJ (2016) Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. Eur J Endocrinol 174(5):651–662. doi:10.1530/eje-15-0391
Greenman Y, Melmed S (1994) Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 79(3):724–729. doi:10.1210/jcem.79.3.7521350
Cuevas-Ramos D, Fleseriu M (2014) Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 52(3):R223–240. doi:10.1530/jme-14-0011
Iacovazzo D, Carlsen E, Lugli F, Chiloiro S, Piacentini S, Bianchi A, Giampietro A, Mormando M, Clear AJ, Doglietto F, Anile C, Maira G, Lauriola L, Rindi G, Roncaroli F, Pontecorvi A, Korbonits M, De Marinis L (2016) Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study. Eur J Endocrinol 174(2):241–250. doi:10.1530/eje-15-0832
Saeger W, Petersenn S, Schofl C, Knappe UJ, Theodoropoulou M, Buslei R, Honegger J (2016) Emerging histopathological and genetic parameters of pituitary adenomas: clinical impact and recommendation for future WHO classification. Endocr Pathol. doi:10.1007/s12022-016-9419-6
Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T, Alafuzoff I, Bollerslev J (2013) 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 98(11):E1730–1739. doi:10.1210/jc.2013-2145
Theodoropoulou M, Tichomirowa MA, Sievers C, Yassouridis A, Arzberger T, Hougrand O, Deprez M, Daly AF, Petrossians P, Pagotto U, Beckers A, Stalla GK (2009) Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly. Int J Cancer 125(9):2122–2126. doi:10.1002/ijc.24602
Lloyd RV, Scheithauer BW, Kuroki T, Vidal S, Kovacs K, Stefaneanu L (1999) Vascular endothelial growth factor (VEGF) expression in human pituitary adenomas and carcinomas. Endocr Pathol 10(3):229–235
Kleinschmidt-DeMasters BK, Lopes MB (2013) Update on hypophysitis and TTF-1 expressing sellar region masses. Brain Pathol 23(5):495–514. doi:10.1111/bpa.12068
Naritaka H, Kameya T, Sato Y, Furuhata S, Otani M, Kawase T (1999) Morphological characterization and subtyping of silent somatotroph adenomas. Pituitary 1(3–4):233–241
Chauvet N, Romano N, Meunier AC, Galibert E, Fontanaud P, Mathieu MN, Osterstock G, Osterstock P, Baccino E, Rigau V, Loiseau H, Bouillot-Eimer S, Barlier A, Mollard P, Coutry N (2016) Combining cadherin expression with molecular markers discriminates invasiveness in growth hormone and prolactin pituitary adenomas. J Neuroendocrinol. doi:10.1111/jne.12352
Ben-Shlomo A, Melmed S (2010) Pituitary somatostatin receptor signaling. Trends Endocrinol Metab 21(3):123–133. doi:10.1016/j.tem.2009.12.003
Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J (2008) The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clin Endocrinol 68(3):458–465. doi:10.1111/j.1365-2265.2007.03065.x
Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, Igreja SC, Chapple JP, Jordan S, Lupp A, Schulz S, Ansorge O, Karavitaki N, Carlsen E, Wass JA, Grossman AB, Korbonits M (2012) Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J Clin Endocrinol Metab 97(8):E1411–1420. doi:10.1210/jc.2012-1111
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Syro, L.V., Rotondo, F., Serna, C.A. et al. Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary. Pituitary 20, 84–92 (2017). https://doi.org/10.1007/s11102-016-0748-8
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DOI: https://doi.org/10.1007/s11102-016-0748-8