ISSN: 1301-2193 E-ISSN: 1308-9846
  • Turkish Journal of
    Endocrinology and Metabolism

Immunohistochemical Subtypes of Growth Hormone-Secreted Pituitary Adenoma and Association with the Clinical Course and Secondary Malignancy
Growth Hormon Sekrete Eden Adenomlarda Subtip Tayininin Klinik Takip ve Akromegali İlişkili Sekonder Malignansi Gelişiminde Rolü
Received Date : 18 Nov 2019
Accepted Date : 22 Jan 2020
Available Online : 14 Feb 2020
Çukurova University Faculty of Medicine, Division of Endocrinology and Metabolism, Adana, Turkey *Çukurova University Faculty of Medicine, Department of Pathology, Adana, Turkey
Doi: 10.25179/tjem.2019-72425 - Makale Dili: EN
Turk J Endocrinol Metab 2020;24:63-71
ABSTRACT
Objective: Most of the acromegaly cases are caused by growth hormonesecreting pituitary adenoma. Pituitary adenomas are classified histologically into sparsely granulated adenoma (SGA) and densely granulated adenoma (DGA). SGAs have been reported to elicit a more aggressive clinical course and therapy resistance. The aim of this study was to investigate the immunohistochemical subtype of patients with pituitary adenoma and their relationship with the clinical course of the disease. Material and Methods: In the period between 2000 and 2016, about 40 (F21, M19) patients with acromegaly who were diagnosed and operated for pituitary adenoma at our university hospital were included in this study. The medical history of patients, duration of the disease, and comorbidities were assessed. Based on current guidelines for acromegaly management, we determined the serum growth hormone [with 75 g “oral glucose tolerance test” (OGTT)], insulin-like growth factor 1 (IGF-1) levels, as well as computed tomography (CT) or magnetic resonance imaging of the pituitary gland. Immunohistochemical staining of postoperative tissue materials and subtypes of pituitary adenomas were evaluated by an experienced cytopathologist. Results: Of the 40 acromegaly patients included in the study, 25 patients were evaluated as sparsely granulated and the remaining 15 patients were evaluated as densely granulated. The mean age of SG adenomas (40.6±9.7 vs. 48.6±5.7, p=0.04) was significantly lower. At the first visit, 64% of SG adenomas were macroadenoma while only 35% of DG adenomas were macroadenoma and the difference was not statistically significant (p=0.43). SG adenomas’ pre-treatment GH, IGF1 values (29.2 ng/mL, 800 ng/mL versus 8.4 ng/mL, 445 ng/mL, p=0.02) and post-treatment GH, IGF1 values (4.1 ng/mL, 440 ng/mL versus 0.4 ng/mL, 152 ng/mL, p=0.03) were significantly higher. While endocrine remission is more common in DG adenomas; organomegaly, abnormal echocardiographic findings (left ventricular hypertrophy) and multinodular goiter were more common in SG adenomas. Malignancy (renal cell Ca, thyroid Ca, larynx Ca) was detected in four patients and histopathological diagnosis of these patients was detected as SG adenoma. Conclusion: The immunohistochemical subtype of the pituitary adenoma may have the potential to affect the clinical course and therapy of acromegaly. SGA is more prone to cavernous sinus invasion, comorbidity and resistance to therapy. Carcinogenesis associated with malignancy was more common in patients with SGA. However, further studies are needed to confirm our findings.
ÖZET
Amaç: Büyüme hormonunu [growth hormone (GH)], sekrete eden adenomlar immünohistokimyasal olarak boyanma paternlerine göre yoğun granüllü (DG) ve seyrek granüllü (SG) olarak gruplandırılmaktadır. Klinik takipte seyrek granüllü adenomlar daha genç hastalarda görülmek ile birlikte, tedaviye daha dirençli olarak bilinirler. Biz bu çalışmada, yoğun granüllü ve seyrek granüllü adenomların akromegali ile ilişkili komorbiditeler (tedavi yanıtı, hipertansiyon, kardiyopulmoner hastalıklar, organomegali, malignansi) açısından ilişkisi olup olmadığını inceledik. Gereç ve Yöntemler: Çalışmaya, 2000-2016 yılları arasında tanı alan 40 (Kadın=21, Erkek=19) akromegali hastasını retrospektif olarak dâhil ettik. Çalışmaya alınan tüm hastaların klinik öykü, fizik muayene bulgusu, tanı anındaki ve tedavi sonrasındaki hormonal, biyokimyasal parametreleri ve görüntüleme (hipofiz manyetik rezonans görüntüleme) bulguları kayıt edildi. Hastaların aldığı tedavi yöntemi (cerrahi, cerrahi+medikal, cerrahi+medikal+radyoterapi) kayıt edildi. Cerrahi sonrası 75 g oral glukoz tolerans testi (OGTT) testine göre GH değerleri kayıt edildi. Hastaların patoloji spesmenleri uzman 2 patolog tarafından tarafsız olarak boyanma paternlerine (DG, SG) göre tekrar değerlendirildi. Bulgular: Çalışmaya alınan 40 akromegali hastasının 25’i seyrek granüllü geriye kalan 15 hasta yoğun granüllü olarak değerlendirildi. SG adenomların yaş ortalaması (40,6±9,7’ye karşı 48,6±5,7, p=0,04) anlamlı olarak daha düşüktü. SG adenomların %64’ü ilk gelişte makroadenom iken, DG adenomların sadece %35’i makroadenom olup istatistiksel olarak anlamlı değildi (p=0,43). SG adenomların tedavi öncesi GH, IGF1 (29,2 ng/mL, 800 ng/mL’ye karşı 8,4 ng/mL, 445 ng/mL, p=0,02) ve tedavi sonrası GH, IGF1 (4,1 ng/mL, 440 ng/mL’ye karşı 0,4 ng/mL, 152 ng/mL, p=0,03) değerleri anlamlı olarak daha yüksek olarak saptandı. Endokrin remisyon DG adenomlarda daha fazla görülürken; organomegali sıklığı, anormal ekokardiyografik bulgular (sol ventrikül hipertrofisi) ve multinodüler guatr SG adenomlarda daha fazla olarak görülmekte idi. Dört hastada malignansi (Renal cell Ca, tiroid Ca, larinks CA) saptanmış olup bu hastaların histopatolojik tanısı SG adenom olarak saptanmıştır. Sonuç: Çalışmamızda, SG adenomlar literatüre uygun olarak daha genç yaşta görülmekle birlikte, tedaviye yanıtları daha az olarak saptandı. Eşlik eden komorbid durumlar (organomegali, kardiyak bulgular, multinodüler guatr) daha fazla eşlik etmekte idi. İstatistiksel olarak anlamlı olmasa da maligniteye eşlik eden 4 akromegali hastasının histopatolojik tanısı seyrek granüllü olarak saptandı. Bu konu ile ilgili yapılacak daha fazla hasta sayısının olduğu çalışmalara ihtiyaç vardır.
Kaynaklar
  1. Kuhn E, Chanson P. Cabergoline in acromegaly. Pituitary. 2016;20:121-128. [Crossref]  [PubMed] 
  2. Lesen E, Granfelt D, Houchard A, Dinet J, Berthon A, Olsson DS, Bjorholt I, Johannsson G. Comorbidities, treatment patterns and cost-of-illness of acromegaly in Sweden: a register-linkage population-based study. Eur J Endocrinol. 2017;176:203-212. [Crossref]  [PubMed] 
  3. Kasper M, Stosiek P, van Muijen GN, Moll R. Cell type heterogeneity of intermediate filament expression in epithelia of the human pituitary gland. Histochemistry. 1898;93:93-103. [Crossref]  [PubMed] 
  4. Obari A, Sano T, Ohyama K, Kudo E, Qian ZR, Yoneda A, Rayhan N,Yamada S. A granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Endocr Pathol. 2008;19:82-91. [Crossref]  [PubMed] 
  5. Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol (Oxf). 2012;76:96-102. [Crossref]  [PubMed] 
  6. Kato M, Inoshita N, Sugiyama T, Tani Y, Shichiri M, Sano T, Yamada S, Hirata Y. Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas. Endocr J. 2012;59:221-228. [Crossref]  [PubMed] 
  7. Syro LV, Rotondo F, Serna CA, Ortiz L, Kovacs K. Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary. Pituitary. 2017;20:84-92. [Crossref]  [PubMed] 
  8. Sanno N, Teramoto A, Osamura RY, Horvath E, Kovacs K, Lloyd RV, Scheithauer BW. Pathology of pituitary tumors. Neurosurg Clin N Am. 2003;14:25-39. [Crossref] 
  9. Vandeva S, Elenkova A, Natchev E, Zacharieva M. Epidemiological variations of aggressive growth hormone-secreting adenomas. Int J Endocr Oncol. 2016;3:245-257. [Crossref] 
  10. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA; Endocrine Society. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933-3951. [Crossref]  [PubMed] 
  11. Clayton PE, Banerjee I, Murray PG, Renehan AG. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol. 2011;7:11-24. [Crossref]  [PubMed] 
  12. Gosink BB, Leymaster CE. Ultrasonic determination of hepatomegaly. J Clin Ultrasound. 1981;9:37-44. [Crossref]  [PubMed] 
  13. Chanson P, Salenave S, Kamenicky P. Acromegaly. Handb Clin Neurol. 2014;124:197-219. [Crossref]  [PubMed] 
  14. Pollak M. Insulin-like growth factor-related signaling and cancer development. Recent Result Cancer Res. 2007;174:49-53. [Crossref]  [PubMed] 
  15. Lee CC, Vance ML, Lopes MB, Xu Z, Chen CJ, Sheehan J. Stereotactic radiosurgery for acromegaly: outcomes by adenoma subtype. Pituitary. 2015;18:326-334. [Crossref]  [PubMed] 
  16. Bakhtiar Y, Hirano H, Arita K, Yunoue S, Fujio S, Tominaga A, Sakoguchi T, Sugiyama K, Kurisu K, Yasufuku-Takano J, Takano K. Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae. Eur J Endocrinol. 2010;163:531-539. [Crossref]  [PubMed] 
  17. Bhayana S, Booth GL, Asa SL, Kovacs K, Ezzat S. The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab. 2005;90:6290-6295. [Crossref]  [PubMed] 
  18. Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary. 2013;16:490-498. [Crossref]  [PubMed] 
  19. Yamada S, Aiba T, Sano T, Kovacs K, Shishiba Y, Sawano S, Takada K. Growth hormone-producing pituitary adenomas: correlations between clinical characteristics and morphology. Neurosurgery. 1993;33:20-27. [Crossref]  [PubMed] 
  20. Kiseljak-Vassiliades K, Xu M, Mills TS, Smith EE, Silveira LJ, Lillehei KO, Kerr JM, Wierman ME. Differential somatostatin receptor (SSTR) 1-5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors. Mol Cell Endocrinol. 2015;417:73-83. [Crossref]  [PubMed]  [PMC] 
  21. Kiseljak-Vassiliades K, Carlson NE, Borges MT, Kleinschmidt-DeMasters BK, Lillehei KO, Kerr JM, Wierman ME. Growth hormone tumor histological subtypes predict response to surgical and medical therapy. Endocrine. 2015;49:231-241. [Crossref]  [PubMed]  [PMC] 
  22. Mendoza V, Sosa E, Espinosa-de-Los-Monteros AL, Salcedo M, Guinto G, Cheng S, Sandoval C, Mercado M. GSPalpha mutations in Mexican patients with acromegaly: potential impact on long term prognosis. Growth Horm IGF Res. 2005;15:28-32. [Crossref]  [PubMed] 
  23. Adams EF, Brockmeier S, Friedmann E, Roth M, Buchfelder M, Fahlbusch R. Clinical and biochemical characteristics of acromegalic patients harboring gsp-positive and gsp-negative pituitary tumors. Neurosurgery. 1993;33:198-203. [Crossref]  [PubMed] 
  24. Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O. Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Eur J Endocrinol. 2013;168:491-499. [Crossref]  [PubMed] 
  25. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004;25:102-152. [Crossref]  [PubMed] 
  26. Espinosa-de-los-Monteros AL, Gonzalez B, Vargas G, Sosa E, Mercado M. Clinical and biochemical characteristics of acromegalic patients with different abnormalities in glucose metabolism. Pituitary. 2011;14:231-235. [Crossref]  [PubMed] 
  27. van Haute FR, Taboada GF, Correa LL, Lima GA, Fontes R, Riello AP, Dominici M, Gadelha MR. Prevalence of sleep apnea and metabolic abnormalities in patients with acromegaly and analysis of cephalometric parameters by magnetic resonance imaging. Eur J Endocrinol. 2008;158:459-465. [Crossref]  [PubMed] 
  28. Kropf LL, Madeira M, Vieria Neto L, Gadelha MR, de Farias ML. Functional evaluation of the joints in acromegalic patients and associated factors. Clin Rheumatol. 2013;32:991-998. [Crossref]  [PubMed] 
  29. Prysor-Jones RA, Jenkin JS. Effect of excessive secretion of growth hormone on tissues of the rat, with particular reference to the heart and skeletal muscle. J Endocrinol. 1980;85:75-82. [Crossref]  [PubMed] 
  30. Boguszewski CL, Boguszewski MC, Kopchick JJ. Growth hormone, insulin-like growth factor system and carcinogenesis. Endokrynol Pol. 2016;67:414-426. [Crossref]  [PubMed] 
  31. Ramos-Levi AM, Marazuela M. Cardiovascular comorbidities in acromegaly: an update on their diagnosis and management. Endocrine. 2017;55:346-359. [Crossref]  [PubMed] 
  32. Mykytyuk MR. Clinical, biochemical and hormonal predictors of the left ventricular hypertrophy in patients with acromegaly. Lik Sprava. 2015;5:34-40.
  33. Sober A, Gorden P, Roth J, T W AvRuskin T. Visceromegaly in acromegaly. Evidence that clinical hepatomegaly or splenomegaly (but not sialomegaly) are manifestations of a second disease. Arch Intern Med. 1974;134:415-417. [Crossref]  [PubMed] 
  34. Cingel-Ristic V, Flybjerg A, Drop SL. The physiological and pathophysiological roles of the GH/IGF-axis in the kidney: lessons from experimental rodent models. Growth Horm IGF Res. 2004;14:418-430. [Crossref]  [PubMed] 
  35. Ciresi A, Amato MC, Vetro C, Lo-Coco E, Galluzzo A, Giordano C. Adrenal morphology and function in acromegalic patients in relation to disease activity. Endocrine. 2009;36:346-354. [Crossref]  [PubMed] 
  36. Yamamoto M, Matsumoto R, Fukuoka H, Iguchi G, Takahaski M, Nishizawa H, Suda K, Bando H, Takahashi Y. Prevalence of simple renal cysts in acromegaly. Intern Med. 2016;55:1685-1690. [Crossref]  [PubMed] 
  37. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-likegrowthfactor-I and risk of breastcancer. Lancet. 1998;351:1393-1396. [Crossref] 
  38. Wolinski K, Stangierski A, Dyrda K, Nowicka K, Pelka M, Iqbal A, Car A, Lazizi M, Bednarek N, Czarnywojtek A, Gurgul E, Ruchala M. Risk of malignant neoplasms in acromegaly: a case-control study. J Endocrinol Invest. 2016;40:319-322. [Crossref]  [PubMed]  [PMC] 
  39. Boguszewski CL, Ayuk J. Management of endocrine disease: acromegaly and cancer: an old debate revisited. Eur J Endocrinol. 2016;175:R147-156. [Crossref]  [PubMed] 
  40. Sekizawa N, Hayakawa E, Tsuchiya K, Yoshimoto T, Akashi T, Fujii T, Yamada S, Hirata Y. Acromegaly associated with multiple tumors. Intern Med. 2009;48:1273-1278. [Crossref]  [PubMed] 
  41. Lang M, Silva D, Dai L, Kshettry VR, Woodard TD, Sindwani R,R PF. Superiority of constructive interference in steady-state MRI sequencing over T1-weighted MRI sequencing for evaluating cavernous sinus invasion by pituitary macroadenomas. J Neurosurg. 2018;1-8. [Crossref]  [PubMed]