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Pituitary Macroadenomas

Pituitary Macroadenomas

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The sellar region is a site of various types of tumors. Pituitary adenomas are the most common. They arise from epithelial pituitary cells and account for 10-15% of all intracranial tumors. Tumors exceeding 10 mm are defined as macroadenomas, and those smaller than 10 mm are termed microadenomas. Most pituitary adenomas are microadenomas.

All tumors should have screening basal hormone measurements, which may include prolactin, thyrotropin, thyroxine, adrenocorticotropin, cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, testosterone, growth hormone, insulinlike growth factor-1 (IGF-1), and alpha subunit glycoprotein.

Dynamic hormone tests are performed to assess the functionality of a tumor and assist in differential diagnosis. They also can be used to assess anterior pituitary reserve.

Pituitary imaging is important in confirming the diagnosis of pituitary macroadenoma and also for determining the differential diagnoses of other sellar lesions. Plain skull radiographs are poor at delineating soft tissues and so have been replaced by computed tomography (CT) scanning and magnetic resonance imaging (MRI).

Visual field testing should be performed, especially in tumors involving the optic chiasm. The severity of visual defects may dictate a more aggressive treatment course.

The goal of treatment for macroadenoma is complete cure. When this is not attainable, reducing tumor mass, restoring hormone function, and restoring normal vision are attempted using medications, surgery, and radiation. Pituitary macroadenomas often require surgical intervention for cure. The exceptions to this rule are the macroprolactinomas, which usually have an excellent response to medical therapy. The tumor size may be diminished but often does not disappear completely. Medical treatment can play a role in reducing tumor size, controlling hormonal excess, or correcting hormonal deficiency.

Pituitary macroadenomas are benign epithelial neoplasms composed of adenohypophysial cells. Primary malignant tumors of the pituitary are extremely rare. Evidence suggests that pituitary adenoma development occurs in several steps, including an irreversible initiation phase followed by tumor promotion.

Pituitary tumor development is a monoclonal process with several contributing factors. Causal contributors include heredity and hormonal influence and genetic mutations. The monoclonal nature of most pituitary tumors suggests that they arise from a mutated pituitary cell. However, the exact pathophysiologic/molecular mechanisms leading to the development of pituitary adenomas remain unknown.

The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from 4 Irish families share a common mutation with a patient from the 18th century who had pituitary tumor–mediated gigantism. [1]

Some pituitary tumors may occur as part of a clinical syndrome. In multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant genetic disorder, pituitary adenomas (most often prolactinomas) occur in association with tumors of the parathyroid and pancreatic islet cells.

In McCune-Albright syndrome, skin lesions and polyostotic fibrous dysplasia occur with hyperfunctioning endocrinopathies. This syndrome results from an activating mutation (somatic mutation) of the alpha subunit of the Gs protein and involves tissues whose response to hormonal signals is mediated by adenylate cyclase. The most common pituitary tumor in McCune-Albright syndrome is somatotropinoma, resulting in acromegaly. Interestingly, a significant proportion of somatotropinomas in sporadic cases of acromegaly harbor the same mutations.

Carney complex is an autosomal dominant disorder characterized by primary pigmented nodular adrenal disease, cutaneous pigmented lesions (lentigines, blue nevi), Sertoli cell tumors of the testes, acromegaly, melanocytic schwannomas, and cardiac myxomas.

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Pituitary tumors are found on autopsy in as many as 25% of unselected cases. The annual incidence of pituitary neoplasms varies from 1-7 cases per 100,000 population based on neurosurgical series.

Morbidity in pituitary macroadenomas varies from incidentally discovered nonfunctioning tumors to disabling macroadenomas. [2] Morbidity results from mass effects (eg, bitemporal hemianopsia), hormonal imbalance (pituitary hormone deficiency due to compression of the normal pituicytes or hormonal excess from the tumor), and patient comorbidities. Significant morbidity is also associated with treatment of these tumors.

No racial predilection exists for pituitary macroadenomas.

Autopsy series show an equal distribution of pituitary tumors between men and women. Corticotropinomas are an exception, occurring mainly in women, with a female-to-male ratio of 4:1. In general, women of childbearing age are diagnosed more frequently with pituitary adenomas than men. The reason for this higher rate of diagnosis is unclear but might be related to the clinical presentation of such patients. Amenorrhea (or menstrual irregularities), which is a relatively common symptom in women with macroadenomas, raises the suspicion of a pituitary lesion.

Tumors affect individuals of all ages, but incidence increases with age, peaking between the third and sixth decades of life.

Chahal HS, Stals K, Unterlander M, et al. AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med. 2011 Jan 6. 364(1):43-50. [Medline].

Vargas G, Gonzalez B, Ramirez C, et al. Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas. Int J Endocrinol. 2015. 2015:756069. [Medline].

Alimohamadi M, Sanjari R, Mortazavi A, Shirani M, Moradi Tabriz H, Hadizadeh Kharazi H, et al. Predictive value of diffusion-weighted MRI for tumor consistency and resection rate of nonfunctional pituitary macroadenomas. Acta Neurochir (Wien). 2014 Dec. 156(12):2245-52. [Medline].

Gupta K, Sahni S, Saggar K, Vashisht G. Evaluation of Clinical and Magnetic Resonance Imaging Profile of Pituitary Macroadenoma: A Prospective Study. J Nat Sci Biol Med. 2018 Jan-Jun. 9 (1):34-8. [Medline].

Greenman Y, Stern N. How should a nonfunctioning pituitary macroadenoma be monitored after debulking surgery?. Clin Endocrinol (Oxf). 2009 Jun. 70(6):829-32. [Medline].

Parhar PK, Duckworth T, Shah P, et al. Decreasing Temporal Lobe Dose with Five-Field Intensity-modulated Radiotherapy for Treatment of Pituitary Macroadenomas. Int J Radiat Oncol Biol Phys. 2009 Dec 14. [Medline].

Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab. 2011 Jul. 96(7):1992-2003. [Medline].

Marek J, Jezkova J, Hana V, et al. Is it possible to avoid hypopituitarism after irradiation of pituitary adenomas by the Leksell gamma knife?. Eur J Endocrinol. 2011 Feb. 164(2):169-78. [Medline].

Wu JS, Shou XF, Yao CJ, et al. Transsphenoidal pituitary macroadenomas resection guided by PoleStar N20 low-field intraoperative magnetic resonance imaging: comparison with early postoperative high-field magnetic resonance imaging. Neurosurgery. 2009 Jul. 65(1):63-70; discussion 70-1. [Medline].

Fomekong E, Maiter D, Grandin C, et al. Outcome of transsphenoidal surgery for Cushing’s disease: a high remission rate in ACTH-secreting macroadenomas. Clin Neurol Neurosurg. 2009 Jun. 111(5):442-9. [Medline].

Theodosopoulos PV, Leach J, Kerr RG, et al. Maximizing the extent of tumor resection during transsphenoidal surgery for pituitary macroadenomas: can endoscopy replace intraoperative magnetic resonance imaging?. J Neurosurg. 2009 Oct 16. [Medline].

Pinar E, Yuceer N, Imre A, Guvenc G, Gundogan O. Endoscopic Endonasal Transsphenoidal Surgery for Pituitary Adenomas. J Craniofac Surg. 2014 Dec 2. [Medline].

Paek SH, Downes MB, Bednarz G, Keane WM, Werner-Wasik M, Curran WJ Jr, et al. Integration of surgery with fractionated stereotactic radiotherapy for treatment of nonfunctioning pituitary macroadenomas. Int J Radiat Oncol Biol Phys. 2005 Mar 1. 61(3):795-808. [Medline].

Han S, Ding X, Tie X, Liu Y, Xia J, Yan A, et al. Endoscopic endonasal trans-sphenoidal approach for pituitary adenomas: Is one nostril enough?. Acta Neurochir (Wien). 2013 Jun 5. [Medline].

Mao ZG, Zhu YH, Tang HL, et al. Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomized trial. Eur J Endocrinol. 2010 Jan 8. [Medline].

Przybylowski CJ, Dallapiazza RF, Williams BJ, et al. Primary versus revision transsphenoidal resection for nonfunctioning pituitary macroadenomas: matched cohort study. J Neurosurg. 2016 May 20. 1-8. [Medline].

Magro E, Graillon T, Lassave J, et al. Complications Related to the Endoscopic Endonasal Transsphenoidal Approach for Nonfunctioning Pituitary Macroadenomas in 300 Consecutive Patients. World Neurosurg. 2016 May. 89:442-53. [Medline].

Sankhla SK, Jayashankar N, Khan GM. Surgical management of selected pituitary macroadenomas using extended endoscopic endonasal transsphenoidal approach: early experience. Neurol India. 2013 Mar-Apr. 61(2):122-30. [Medline].

Berkmann S, Fandino J, Zosso S, et al. Intraoperative magnetic resonance imaging and early prognosis for vision after transsphenoidal surgery for sellar lesions. J Neurosurg. 2011 Sep. 115(3):518-27. [Medline].

Hisanaga S, Kakeda S, Yamamoto J, et al. Pituitary Macroadenoma and Visual Impairment: Postoperative Outcome Prediction with Contrast-Enhanced FIESTA. AJNR Am J Neuroradiol. 2017 Nov. 38 (11):2067-72. [Medline].

Thawani JP, Ramayya AG, Pisapia JM, Abdullah KG, Lee JY, Grady MS. Operative Strategies to Minimize Complications Following Resection of Pituitary Macroadenomas. J Neurol Surg B Skull Base. 2017 Apr. 78 (2):184-90. [Medline].

Johnston PC, Kennedy L, Hamrahian AH, et al. Surgical outcomes in patients with Cushing’s disease: the Cleveland clinic experience. Pituitary. 2017 Mar 6. [Medline].

Elhateer H, Muanza T, Roberge D, et al. Fractionated stereotactic radiotherapy in the treatment of pituitary macroadenomas. Curr Oncol. 2008 Dec. 15(6):286-92. [Medline]. [Full Text].

Schalin-Jäntti C, Valanne L, Tenhunen M, et al. Outcome of Fractionated Stereotactic Radiotherapy in Patients with Pituitary Adenomas Resistant to Conventional Treatments: a 5.25- yr Follow-up Study. Clin Endocrinol (Oxf). 2009 Dec 18. [Medline].

Watts AK, Easwaran A, McNeill P, Wang YY, Inder WJ, Caputo C. Younger age is a risk factor for regrowth and recurrence of nonfunctioning pituitary macroadenomas: Results from a single Australian centre. Clin Endocrinol (Oxf). 2017 Sep. 87 (3):264-71. [Medline].

Raverot G, Burman P, McCormack AI, et al. European Society of Endocrinology clinical practice guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2017 Oct 18. [Medline]. [Full Text].

Mello PA, Naves LA, Pereira Neto A, Oliveira EH, Ferreira IC, Araújo Júnior AS, et al. Clinical and laboratorial characterization and post-surgical follow-up of 87 patients with non-functioning pituitary macroadenomas. Arq Neuropsiquiatr. 2013 May. 71(5):307-12. [Medline].

Laws ER Jr, Iuliano SL, Cote DJ, Woodmansee W, Hsu L, Cho CH. A Benchmark for Preservation of Normal Pituitary Function After Endoscopic Transsphenoidal Surgery for Pituitary Macroadenomas. World Neurosurg. 2016 Jul. 91:371-5. [Medline].

Hwang YC, Chung JH, Min YK, et al. Comparisons between macroadenomas and microadenomas in Cushing’s disease: characteristics of hormone secretion and clinical outcomes. J Korean Med Sci. 2009 Feb. 24(1):46-51. [Medline]. [Full Text].

Fernandez-Balsells MM, Murad MH, Barwise A, et al. Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2011 Apr. 96(4):905-12. [Medline].

James R Mulinda, MD, FACP Consulting Staff, Department of Endocrinology, Endocrinology Associates, Inc

James R Mulinda, MD, FACP is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Yoram Shenker, MD Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison

Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Dimitris A Papanicolaou, MD 

Dimitris A Papanicolaou, MD is a member of the following medical societies: American College of Physicians, Endocrine Society, Royal Society of Medicine

Disclosure: Nothing to disclose.

Pituitary Macroadenomas

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