Abstract
Ectopic pituitary adenomas are defined by the presence of adenomatous pituitary tissue outside the sella and distinctly separate from the pituitary gland. Ectopic ACTH-secreting pituitary adenomas (EAPAs) are a rare cause of Cushing’s syndrome. Detecting these radiologically can prove difficult, in part, due to their typically small size and unpredictable anatomical location. In ACTH-dependent Cushing’s syndrome, if, despite comprehensive testing, the source of excess ACTH remains occult (including negative work up for ectopic ACTH syndrome) thought should be given to the possibility of the patient harboring an EAPA. In most cases, ectopic ACTH pituitary adenomas within the sphenoid sinus will manifest with symptoms of hormonal excess, have an obvious sphenoid sinus mass on pre-operative imaging and will demonstrate resolution of hypercortisolism after surgical excision if located and removed. Twenty cases of EAPAs have been reported in the literature to date. This paper will review the current literature on all previously reported EAPAs within the sphenoid sinus in addition to the current case.
Similar content being viewed by others
References
C. Steffensen, A.M. Bak, K.Z. Rubeck, J.O. Jorgensen, Epidemiology of Cushing’s syndrome. Neuroendocrinology 92(1), 1–5 (2010)
R.N. Clayton, D. Raskauskiene, R.C. Reulen, P.W. Jones, Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J. Clin. Endocrinol. Metab. 96, 632–642 (2011)
Z.K. Hassan-Smith, M. Sherlock, R.C. Reulen, W. Arlt, J. Ayuk, A.A. Toogood, M.S. Cooper, A.P. Johnson, P.M. Stewart, Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J. Clin. Endocrinol. Metab. 97(4), 1194–1201 (2012)
R.A. Feelders, S.J. Pulgar, A. Kempel, A.M. Pereira, The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur. J. Endocrinol. 167, 311–326 (2012)
I. Ilias, D.J. Torpy, K. Pacak, N. Mullen, R.A. Wesley, L.K. Nieman, Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J. Clin. Endocrinol. Metab. 90, 4955–4962 (2005)
B.L. Wajchenberg, B.B. Mendonca, B. Liberman, M.A. Pereira, P.C. Carneiro, A. Wakamatsu, M.A. Kirschner, Ectopic adrenocorticotropic hormone syndrome. Endocr. Rev. 15, 752–787 (1994)
A.M. Isidori, G.A. Kaltsas, C. Pozza, C.V. Frajese, J. Newell-Price, R.H. Reznek, P.J. Jenkins, J.P. Monson, A.B. Grossman, G.M. Besser, The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management and long-term follow-up. J. Clin. Endocrinol. Metab. 91, 371–377 (2006)
C. Wilson, T. Mindermann, J. Tyrell, Extrasellar, intracavernous sinus adrenocorticotropin releasing adenoma causing Cushing’s disease. J. Clin. Endocrinol. Metab. 80, 1774–1777 (1995)
A. Matsumura, K. Meguro, Y. Tomono, T. Nose, Functioning ectopic supradiaphragmatic pituitary adenoma. Neurosurgery 35, 343–344 (1994)
M. Boscaro, M.G. Arnaldi, Approach to the patient with possible Cushing’s syndrome. J. Clin. Endocrinol. Metab. 94, 3121–3131 (2009)
P. Rasmussen, J. Lindholm, Ectopic pituitary adenomas. Clin. Endocrinol. 11, 69–74 (1979)
A. Hori, Suprasellar peri-infundibular ectopic adenohypophysis in fetal and adult brains. J. Neurosurg. 63, 113–115 (1985)
A.N. Martins, G.J. Hayes, L.G. Kempe, Invasive pituitary adenomas. J. Neurosurg. 22, 268–276 (1965)
A. Matsumura, K. Meguro, M. Doi, H. Tsurushima, Y. Tomono, Suprasellar ectopic pituitary adenoma: case report and review of the literature. Neurosurgery 26, 681–685 (1990)
A. Tal, Cushing’s disease caused by ectopic pituitary adenoma within the pituitary stalk. South. Med. J. 86, 249–250 (1993)
R.J. Weil, A.O. Vortmeyer, L.K. Nieman, H.L. Devroom, J. Wanebo, E.H. Oldfield, Surgical remission of pituitary adenomas confined to the neurohypophysis in Cushing’s disease. J. Clin. Endocrinol. Metab. 91(7), 2656–2664 (2006)
R.B. Mason, L.K. Nieman, J.L. Doppman, E.H. Oldfield, Selective excision of adenomas originating in or extending into the pituitary stalk with preservation of pituitary function. J. Neurosurg. 87, 343–351 (1997)
J.A. Veit, B. Boehm, M. Luster, A. Scheuerle, N. Rotter, G. Rettinger, M. Scheithauer, Detection of paranasal ectopic adrenocorticotropic hormone secreting pituitary adenoma by Ga-68 DOTANOC positron emission tomography computed tomography. Laryngoscope 123, 1132–1135 (2013)
T. Ohnishi, N. Arita, T. Yoshimine, S. Mori, Intracavernous sinus ectopic adrenocorticotropin secreting tumours causing therapeutic failure in transsphenoidal surgery for Cushing’s disease. Acta Neurochir. 142, 855–864 (2000)
M. Hamon, C. Coffin, P. Courtheoux, J. Theron, Y. Reznik, Cushing disease caused by an ectopic intracavernous pituitary microadenoma: case report and review of the literature. J. Comput. Assist. Tomogr. 27, 424–426 (2003)
E. Horvath, K. Kovacs, D.W. Killinger, H.S. Smyth, M.E. Platts, W. Singer, Silent corticotrophic adenomas of the human pituitary gland. A histologic immunocytologic and ultrastructural study. Am. J. Pathol. 98, 617–638 (1980)
K. Kovacs, E. Horvath, Silent corticotroph adenoma, in Tumors of the pituitary gland, eds. K. Kovacs, E. Horvath. Atlas of Tumor Pathology, second series, Fascicle 21. (Armed Forces Institute of Pathology, Washington, DC, 1986), pp. 150–164
L. Hou, T. Harshbarger, M.K. Herrick, V. Tse, Suprasellar adrenocorticotropic hormone secreting ectopic pituitary adenoma: case report and literature review. Neurosurgery 50, 618–625 (2002)
N. Hattori, T. Ishihara, S. Saiwai, K. Moridera, M. Hino, K. Ikekubo, H. Kurahachi, Ectopic prolactinoma on MRI. J. Comput. Assit. Tomogr. 18, 936–938 (1994)
D. Madonna, A. Kindler, A.M. Soliman, Ectopic growth hormone secreting pituitary adenoma in the sphenoid sinus. Ann. Otol. Rhinol. Laryngol. 110, 99–101 (2001)
L.J. Kim, J.D. Klopfenstein, M. Cheng, M. Nagul, S. Coons, C. Fredenberg, D.G. Brachman, W.L. White, Ectopic intracavernous sinus adrenocorticotropic hormone secreting microadenoma: could this be a common cause of failed transsphenoidal surgery in Cushing’s disease. J. Neurosurg. 98, 1312–1317 (2003)
G.B. Mulligan, C. Faiman, M. Gupta, L. Kennedy, B. Hatipoglu, F. Hui, R.J. Weil, A.H. Hamrahian, Prolactin measurement during inferior petrosal sinus sampling improves the localization of pituitary adenomas in Cushing’s disease. Clin. Endocrinol. 77(2), 268–274 (2012)
E.H. Oldfield, A.O. Vortmeyer, Development of a histological pseudocapsule and its use as a surgical capsule in the excision of pituitary tumors. J. Neurosurg. 104(1), 7–19 (2006)
R. Pivonello, M.C. DeMartino, M. DeLeo, G. Lombardi, A. Calao, Cushing’s syndrome. Endocrinol. Metab. Clin. N. Am. 37, 135–149 (2008)
O. Ciocca, L. Puy, A. Stati, Identification of seven hormone producing cell types in the human pharyngeal hypophysis. J. Clin. Endocrinol. Metab. 60, 212–216 (1985)
R. Melchionna, R. Moore, The pharyngeal pituitary gland. Am. J. Pathol. 14, 763–771 (1938)
H. Kammer, R. George, Cushing’s disease in a patient with an ectopic pituitary adenoma. JAMA 246(23), 2722–2724 (1981)
W. Burch, R. Kramer, P. Kenan, C.B. Hammond, Cushing’s disease caused by an ectopic pituitary adenoma within the sphenoid sinus. NEJM 312, 587–588 (1985)
R.V. Lloyd, W.F. Chandler, K. Kovacs, N. Ryan, Ectopic pituitary adenomas with normal anterior pituitary glands. Am. J. Surg. Pathol. 10, 546–552 (1986)
D.E. Schteingart, W.F. Chandler, R.V. Lloyd, G. Ibarra-Perez, Cushing’s syndrome caused by an ectopic pituitary adenoma. Neurosurgery 21, 223–227 (1987)
S.M. Slonim, H.A. Haykal, G.W. Cushing, S.R. Freidberg, A.K. Lee, MRI appearances of an ectopic pituitary adenoma: case report and review of the literature. Neuroradiology 35, 546–548 (1993)
H. Morita, K. Yasuda, K. Nakashima, N. Noritake, M. Murayama, K. Shimokawa, N. Yamakita, T. Sano, N. Sasano, K. Miura, Cushing’s syndrome caused by an ectopic pituitary adenoma of the sphenoid sinus: adrenal crisis after partial resections of the adenoma. Endocr. Pathol. 15, 123–130 (1994)
C.L. Coire, E. Horvath, K. Kovacs, H.S. Smyth, S. Ezzat, Cushing’s syndrome from an ectopic pituitary adenoma with peliosis: a histological, immunohistochemical and ultrastructural study and review of the literature. Endocr. Pathol. 8, 65–74 (1997)
F. Esteban, I. Ruiz-Avila, R. Vilchez, C. Gamero, M. Gomez, A. Mochon, Ectopic pituitary adenoma in the sphenoid causing Nelson’s syndrome. J. Laryngol. Otol. 111, 565–567 (1997)
R.M. Pluta, L. Nieman, J.L. Doppman, J.C. Watson, N. Tresser, D.A. Katz, E.H. Oldfield, Extrapituitary parasellar microadenoma in Cushing’s disease. J. Clin. Endocrinol. Metab. 84, 2912–2923 (1999)
H. Bethge, H.W. Arlt, U. Zimmermann, G. Klingelhoffer, G. Wittenberg, W. Saeger, B. Allolio, Cushing’s syndrome due to an ectopic ACTH-secreting pituitary tumour mimicking occult paraneoplastic ectopic ACTH production. Clin. Endocrinol. 51, 809–814 (1999)
J. Suzuki, F. Otsuka, T. Ogura, M. Kishida, M. Takeda, T. Tamiya, T. Nishioka, Y. Tanaka, K. Hashimoto, H. Makino, An aberrant ACTH-producing ectopic pituitary adenoma in the sphenoid sinus. Endocr. J. 51, 97–103 (2004)
M. Al Gahtany, J. Bilbao, K. Kovacs, E. Horvath, H.S. Smyth, Juxtaposition of an ectopic corticotroph adenoma of the sphenoid sinus with orthotopic intrasellar corticotroph hyperplasia in a patient with Cushings disease. J. Neurosurg. 98, 891–896 (2003)
R.K. Zerikly, E. Eray, C. Faiman, R.R. Lorenz, R.J. Weil, A.H. Hamrahian, Cyclic Cushings syndrome due to an ectopic pituitary adenoma. Nat. Clin. Pract. Endocrinol. Metab. 5, 174–179 (2008)
M. Trulea, M. Patey, B. Chaufour-Higel, F. Bouquigny, A. Longuebray, P. Rousseaux, C. Pasqual, A. Tabarin, B. Delemer, An unusual case of ectopic adrenocorticotropin secretion. J. Clin. Endocrinol. Metab. 94, 384–385 (2009)
K. Suzuki, Y. Hattori, C. Aoki, A. Nakano, A. Tomizawa, H. Kase, K. Kasai, An ACTH secreting pituitary adenoma within the sphenoid sinus. Inter. Med. 49, 763–766 (2010)
B.T. Yang, V.F. Chong, Z.C. Wang, J.F. Xian, Q.H. Chen, Sphenoid sinus ectopic pituitary adenomas: CT and MRI findings. Br. J Radiol. 83, 218–224 (2010)
M.J. Willhauck, G. Popperl, W. Rachinger, A. Giese, C.J. Auernhammer, C. Spitzweg, An unusual case of ectopic ACTH syndrome. Exp. Clin. Endocrinol. Diabetes 120, 63–67 (2012)
U. Srikantha, K. Khanapure, M. Mohan, R.G. Varma, Sphenoidal ectopic ACTH secreting pituitary adenoma. JPMS 2, 59–63 (2012)
L.D. Thompson, R.R. Seethala, S. Muller, Ectopic sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary gland: a clinicopathologic and immunophenotypic study of 32 cases with a comprehensive review of the English literature. Head Neck Pathol. 6, 75–100 (2012)
M. Ritter, T. Burkhardt, S. Schmid, C. Bernreuther, B. Winterberg, H. Lehnert, J. Flitsch, Pitfalls in Cushing’s disease:report of an ectopic ACTH producing pituitary adenoma in the sphenoid sinus. Endocr. Abstr. 29, P1458 (2012)
M. Gabriel, C. Decristoforo, D. Kendler, G. Dobrozemsky, D. Heute, C. Uprimny, P. Kovacs, E. von Guggenberg, R. Bale, I.J. Virgolini, 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J. Nucl. Med. 48, 508–518 (2007)
A.R. Haug, C.J. Auernhammer, B. Wängler, G.P. Schmidt, C. Uebleis, B. Goke, P. Cumming, P. Bartenstein, R. Tiling, M. Hacker, 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J. Nucl. Med. 51, 1349–1356 (2010)
I. Kayani, J.B. Bomanji, A. Groves, A.G. Conway, S. Gacinovic, T. Win, J. Dickson, M. Caplin, P.J. Ell, Functional imaging of neuroendocrine tumors with combined PET/CT using 68 Ga-DOTATATE (DOTA-DPhe1, Tyr3-octreotate) and 18F-FDG. Cancer 112, 2447–2455 (2008)
J.J. Wind, R.R. Lonser, L.K. Nieman, H.L. DeVroom, R. Chang, E.H. Oldfield, The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 98(6), 2285–2293 (2013)
E.H. Oldfield, J.L. Doppman, L.K. Nieman, G.P. Chrousos, D.L. Miller, D.A. Katz, G. B. Cutler Jr, D.L. Loriaux, Petrosal sinus sampling with and without corticotropin releasing hormone for the differential diagnosis of Cushing’s syndrome. NEJM 325, 897–905 (1991)
G. Zada, P.K. Agarwall, S. Mukundan, S.I. Dunn, A.J. Golby, E.R. Laws Jr, The neurosurgical anatomy of the sphenoid sinus and sellar floor in endoscopic transsphenoidal surgery. J. Neurosurg. 14, 1319–1330 (2011)
V.R. Ramakrishnan, J.D. Suh, J.Y. Lee, B.W. Jr, O’Malley, M.S. Grady, J.N. Palmer, Sphenoid sinus anatomy and suprasellar extension of pituitary tumors. J. Neurosurg. 119, 669–674 (2013)
A. Calao, M. Boscaro, D. Ferone, F. F. Casanueva, Managing Cushing’s disease: the state of the art. Endocrine. Ahead of print (2014)
P.W. Smith, K.C. Turza, C.O. Carter, M.L. Vance, E.R. Laws, J.B. Hanks, Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J. Am. Coll. Surg. 208, 1059–1064 (2009)
D. Ferone, C. Pivonello, G. Vitale, M.C. Zatelli, A. Calao, R. Pivonello, Molecular basis of pharmacological therapy in Cushing’s disease. Endocrine. 46(2), 181–198 (2014)
A. Calao, S. Petersenn, J. Newell-Price, J.W. Findling, F. Gu, M. Maldonado, U. Schoenherr, D. Mills, L.R. Salgado, B.M.K, Biller, A 12-month phase 3 study of pasireotide in Cushing’s disease. NEJM 366, 914–924 (2012)
J.D. Carmichael, M. Fleseriu, Mifepristone: is there a place in the treatment of Cushing’s disease? Endocrine 44, 20–32 (2013)
M. Fleseriu, B.M. Biller, J.W. Findling, M.E. Molitch, D.E. Schteingart, C. Gross, Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 97(6), 2039–2049 (2012)
J. Estrada, M. Boronat, M. Mielgo, R. Magallon, I. Millan, S. Diez, T. Lucas, B. Barcelo, The long term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. NEJM 336, 172–177 (1997)
Acknowledgments
We would like to thank Dr. Richard Prayson and Dr. Daniel Lockwood for providing the histological pictures and pituitary imaging, respectively.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Johnston, P.C., Kennedy, L., Weil, R.J. et al. Ectopic ACTH-secreting pituitary adenomas within the sphenoid sinus. Endocrine 47, 717–724 (2014). https://doi.org/10.1007/s12020-014-0313-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-014-0313-z