Transsphenoidal Surgery for Mixed Pituitary Gangliocytoma-Adenomas

Accepted Manuscript Transsphenoidal surgery for mixed pituitary gangliocytoma-adenomas Matthew J. Shepard, MD, Mohamed A. Elzoghby, MD, Daffer Ghanim, BS, M. Beatriz S. Lopes, MD, PhD, John A. Jane, Jr., MD PII:

S1878-8750(17)31484-5

DOI:

10.1016/j.wneu.2017.08.174

Reference:

WNEU 6424

To appear in:

World Neurosurgery

Please cite this article as: Shepard MJ, Elzoghby MA, Ghanim D, Lopes MBS, Jane Jr. JA, Transsphenoidal surgery for mixed pituitary gangliocytoma-adenomas, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.08.174. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Shepard

Transsphenoidal surgery for mixed pituitary gangliocytomaadenomas

a

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Matthew J. Shepard, MDa; Mohamed A. Elzoghby, MDc; Daffer Ghanim, BSd; M. Beatriz S. Lopes, MD, PhD a,b, John A. Jane Jr., MDa

tel: 434-243-5749 fax: 434-243-5204 email: [email protected]

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Corresponding Author/Reprint Requests: John A. Jane, Jr. M.D. Professor of Neurosurgery and Pediatrics Department of Neurosurgery University of Virginia Health System PO Box 800212 Charlottesville, VA 22908-0711

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Department of Neurologic Surgery, University of Virginia Health Center, Charlottesville, VA Department of Pathology, University of Virginia Health Center, Charlottesville, VA c Department of Neurosurgery, Ain Shams University, Cairo, Egypt d James Cook University, Townsville, Queensland, Australia b

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Key Words: Acromegaly, Gangliocytoma, Pituitary Adenoma, Transphenoidal Surgery

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Abbreviations: ACTH - Adrenocorticotropic hormone CNS - Central nervous system CRH - Corticotropin-releasing hormone FSH – Follicle-stimulating hormone GKRS - Gamma knife radiosurgery GH – Growth hormone GHRH - Growth hormone releasing hormone GnRH - Gonadotropin releasing hormone GTR – Gross total resection IGF-1 – Insulin like growth factor 1 IRB – Institutional review board LH – Luteinizing hormone MRI - Magnetic resonance imaging MGA - Mixed gangliocytoma-adenoma PIT-1 - pituitary-specific positive transcription factor 1 PRL – Prolactin TRH – Thyrotropin releasing hormone

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ACCEPTED MANUSCRIPT Shepard Abstract: Objective: Most sellar gangliocytomas are discovered with a concurrent pituitary adenoma, also known as a mixed gangliocytoma-adenoma (MGA). MGAs are rare with less than 100 cases

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reported in the literature and only one previously documented surgical series. As MGAs are radiologically indistinguishable from pituitary adenomas, their diagnosis is often made following surgery. This, combined with the paucity of clinical outcome data for these tumors, makes their

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diagnosis and management challenging. Thus, the clinical presentation and outcomes of 10 individuals who were diagnosed with a MGA at a single institution are described.

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Methods: A retrospective case series was performed on patients who were diagnosed with a combined sellar gangliocytoma-adenoma between 1993 and 2016.

Results: 10 patients with a mean age of 44 years (range 28-63 years) were diagnosed with a MGA. The mean tumor size was 1.6cm (range 0.4-2.4cm). Five patients presented with

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acromegaly and one with recurrent Cushing’s disease. Transsphenoidal surgery was performed in all instances and gross total resection was achievable in 70% of individuals. Histologically, 9/10 MGAs were mixed somatotroph adenoma-gangliocytomas. The median follow-up was 74

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months (range 2-180 months). Following adjuvant treatment (n=3), all patients with acromegaly (n=4) achieved biochemical remission and no patient following surgery had recurrence of their

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pituitary tumor with a median radiographic follow-up of 48 months. Conclusions: Mixed gangliocytoma-adenomas are often associated with a hypersecretory adenoma. Transphenoidal surgery is tolerated well in most instances and in combination with adjuvant therapy, low rates of recurrence and reversal of pre-operative endocrinopathy can be expected.

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ACCEPTED MANUSCRIPT Shepard Funding: This research did not receive any specific grant from funding agencies in the public, commercial,

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or not-for-profit sectors.

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ACCEPTED MANUSCRIPT Shepard Introduction: Gangliocytomas are benign tumors derived from ganglion cells of the central and peripheral nervous system.1,2 These slow growing tumors are rare and account for less than 1% of all

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intracranial neoplasms.2 Gangliocytomas have the potential to manifest anywhere within central nervous system (CNS) but have been described to occur within the sella in fewer than 100

cases.1 Over two-thirds of sellar gangliocytomas present with a concurrent pituitary adenoma and

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have been referred to by some authors as a mixed pituitary gangliocytoma-adenoma (MGA).3 In the majority of MGAs, a hypersecretory state is observed with growth hormone (GH) being the

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commonest secreted hormone.4 To date, only one surgical series has reported outcomes on patients with MGAs.3 As such, the optimal management and long-term outcomes of these rare sellar lesions remain ill defined. Herein we report a series of mixed sellar gangliocytomaadenomas and describe the 10 cases of MGAs treated at the University of Virginia Health

Materials and Methods:

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System between 1993 and 2016.

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An institutional review board (IRB) approved retrospective case series was completed of all patients who harbored a diagnosis of combined sellar gangliocytoma and pituitary adenoma. In

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all cases, the diagnosis was histologically confirmed by morphology, immunohistochemical studies and, when available, by ultrastructural analysis. The degree of surgical resection was determined on 3-month post-operative magnetic resonance imaging (MRI). Gross total resection (GTR) was defined as no apparent disease on 3-month MRI while subtotal resection was defined as persistent tumor observed on at least two MRIs. In instances where post-operative MRIs could not be reviewed, GTR was approximated using the surgeon’s assessment of total tumor

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ACCEPTED MANUSCRIPT Shepard removal. All imaging was reviewed by a neuroradiologist and neurosurgeon. Patient medical records, radiologic studies, pathologic reports and laboratory studies were reviewed. Clinical improvement was defined as documented improvement in pre-operative symptoms as judged by

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a clinician. Hormonal remission was defined as normalization of pre-operative endocrinopathy. Remission from Cushing’s disease was defined as immediate hypocortisolemia (cortisol< 5 ng/dl). Remission of Acromegaly required normalization of IGF-1 and either a random GH of

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<1, or a nadir GH of <0.4 ng/mL during an oral glucose tolerance test at the 2-month post-

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operative follow up appointment.

Results: Patient Characteristics

Ten patients with MGA were identified upon review of our IRB approved pathologic database.

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Baseline patient characteristics are summarized in Table 1. The median age of the patients at the time of surgical resection was 44 years (range 28-63). The majority of patients in this series were female (70%) and 90% of the MGAs were classified as macroadenomas. The mean tumor

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diameter was 1.6cm (range 0.4-2.4cm). Three patients had documented cavernous sinus invasion on pre-operative MRI. Five patients had clinical and laboratory data consistent with the

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diagnosis of acromegaly. One patient had recurrent Cushing’s disease and in 4 cases, the sellar tumor was found incidentally or presented with signs and symptoms of a sellar mass. One patient (Case 8) harbored a clinically silent GH adenoma with elevated Insulin-like growth factor 1 (IGF-1) levels but no clinical features of acromegaly (IGF-1 level 439 ng/mL). Definitive clinically non-functioning sellar adenomas were present in 3 cases. Pre-operative prolactin

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ACCEPTED MANUSCRIPT Shepard (PRL) levels were normal for all but one patient who had a mildly elevated PRL level (Case 1, 32ng/mL).

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Surgical Outcomes

Transsphenoidal surgery was performed in all patients. An endonasal submucosal microscopic approach was used in 7 cases and an endoscopic, endonasal approach was used in the remaining

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3. There was one post-operative cerebrospinal fluid leak that required lumbar drainage and

surgical repair with a nasoseptal flap (Case 10). No patient experienced a new visual field deficit

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postoperatively. One patient (Case 1) developed transient post-operative diabetes insipidus. Case 6 developed post-operative hypogonadism and adrenal insufficiency and is maintained on hormonal replacement therapy. At the time of surgery, total tumor removal was achieved in 7 instances (70%) and partial resection was achieved in 3 individuals (30%). 7/10 patients had

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post-operative imaging available for review. Three patients (3/7, 43%) had expected residual tumor on their 3-month post-operative MRI (Case 1, Case 6 and Case 10). Case 1 and case 6 underwent post-operative gamma knife radiosurgery (GKRS) while Case 10 required fractioned

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radiation given the proximity of residual tumor to the optic chiasm. Tumor stability was achieved for all 3 patients with subtotal resection with a median radiographic follow up of 80

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months (range 13-180 months). None of the 7 patients with radiographic GTR at 3 months exhibited tumor progression at last follow up.

Clinical and Endocrinologic Follow Up 7 of the 10 cases had clinical follow-up available and outcomes are summarized in Table 2. Median clinical follow up was 74 months (range 2-180) with median radiographic follow up of

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ACCEPTED MANUSCRIPT Shepard 48 months (range 3-180 months). Cases 1, 2, 6 and 10 had clinical and biochemical evidence of acromegaly pre-operatively. Following surgery, Case 1, 6 and 10 failed to achieve biochemical remission of their disease. We therefore treated these individuals with adjuvant radiation. Case 6

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additionally underwent treatment with pegvisomant. At last follow up, all 4 patients who were diagnosed pre-operatively with acromegaly had clinical improvement and were deemed to be in remission by an independent endocrinologist. The four cases of acromegaly with documented

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clinical follow up had normal IGF-1 levels at last clinical evaluation (Case 1 – 131 ng/mL; Case 2 - 151 ng/mL; Case 4 - 160 ng/mL and Case 10 - 310 ng/mL). Post-operative PRL levels were

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available for all patients with follow up and normal in each instance.

Pathologic Review:

All tumors were histologically composed of typical neuroendocrine adenomatous cells and

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ganglionic elements in variable proportions consistent with a MGA as summarized in Figure 1. In nine cases, the diagnosis was consistent with a mixed somatotroph adenoma-gangliocytoma despite 4 of these 9 patients presenting clinically with non-functioning adenomas. The

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somatotroph adenoma component was a sparsely-granulated adenoma in 8 of 9 cases and the remaining case was a mixed sparsely and densely-granulated adenoma. In 6 of 9 cases, the

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adenomas were also immunoreactive for other pituitary hormones including PRL in five cases, and focal β-luteinizing hormone (LH) and β-follicle stimulating hormone (FSH) in one case. In all cases, the adenomatous cells were strongly immunoreactive for the acidophilic-lineage transcription factor pituitary-specific positive transcription factor 1 (Pit-1). The majority of the cases show isolated ganglionic cells embedded in a neuropil-like matrix. The ganglionic cells contain central, vesicular nuclei and prominent nucleoli and large cytoplasm with Nissl bodies;

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ACCEPTED MANUSCRIPT Shepard some ganglionic cells showed binucleation. Other cells have an intermediate or transitional appearance with large cytoplasm and large nuclei, but lacking Nissl bodies. The ganglionic cells variably expressed the neuronal markers NeuN, neurofilament proteins, and MAP2 in all tumors.

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Pit-1 was expressed by small numbers of typical ganglionic cells and some transitional cells in 6/9 cases. In three cases, ultrastructural analysis of the tumor confirmed the typical appearance of sparsely-granulated somatotroph cells with cells containing sparse numbers of secretory

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granules and cytoplasmic fibrous bodies; in one of the three cases, mature ganglionic cells with rich Nissl substance were also present intermixed with the somatotroph cells. The patient with

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recurrent Cushing’s showed similar histopathological features of a mixed adenomagangliocytoma with adenomatous cells strongly immunoreactive for adrenocorticotropic hormone (ACTH). Ultrastructural analysis of the later tumor was remarkable for welldifferentiated corticotroph cells with large numbers of secretory granules and focal accumulation

microscopy.

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Discussion:

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of cytokeratin; no ganglionic elements were present in the sample analyzed by electron

Sellar gangliocytomas are rare manifestations of an otherwise benign neuronal derived tumor.

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The majority of cases of sellar gangliocytomas occur in combination with pituitary adenomas but these tumors are rare, representing less than 1% of all sellar tumors.2-30 As imaging characteristics of mixed gangliocytoma-adenoma tumors are similar to pituitary adenomas, the diagnosis of MGAs is often made after surgical resection on the basis of pathologic analysis.3 Therefore, given the limited surgical series detailing the natural history of these rare tumors, it

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ACCEPTED MANUSCRIPT Shepard has not been well characterized in the literature whether MGAs will behave in a different manner compared to traditional pituitary adenomas.

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Qiao et al. have published the only study examining surgical outcomes of MGAs.3 In their cohort of 23 patients diagnosed with a sellar gangliocytoma, 16 patients were diagnosed with a

combined pituitary adenoma-gangliocytoma. The median age at presentation was 42 years and

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all patients were female. Similar to our results, 50% of patients in Qiao’s series presented with acromegaly and 10 patients in their cohort had elevated levels of GH. In their series, surgical

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resection was performed in all patients and gross total resection was achieved in 87.5%. The instances of subtotal resection in their work was attributed to cavernous sinus invasion. Endocrinopathy was reversed in 78% of their cases and there was evidence of tumor recurrence in only one patient after five years. All but one patient in their study achieved remission from

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acromegaly. Our data suggest similar surgical outcomes for MGAs with GTR achievable in the majority of cases. While three patients had evidence of residual tumor on post-operative MRI requiring subsequent treatment, no patient had recurrence or progression of their adenoma after a

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median clinical follow up 6 years. In prior studies, biochemical remission was achievable in up to 61% of patients with acromegaly with a macroadenoma.31 In the series reported herein, only

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one of four patients with acromegaly achieved biochemical remission with surgery alone. Given the limited follow up and small number of subjects included in this study, it is difficult to know whether the lower rate of surgical remission for patients with acromegaly is reflective of a true difference from pure GH adenomas or related to sample error. In the work by Jane et al, none of the patients who had persistently elevated IGF-1 levels post-operatively achieved remission following stereotactic radiosurgery which is not the case for the two patients reported in this

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ACCEPTED MANUSCRIPT Shepard study.31 Thus, our results when examined in combination with Qiao’s series suggest that the natural history of combined gangliocytomas and adenomas does not appear to be significantly different than hyper-secreting pituitary adenomas provided that adequate surgical resection and

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adjuvant therapy are implemented.

In each case reported herein, there was no radiographic or clinical indication that would have

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alerted the surgeon to the presence of a MGA. Therefore, all tumors were approached with the presumed understanding that the sellar lesion represented either a non-functional or hyper-

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secreting adenoma. As a result, the surgical approach was that of a standard microscopic or endoscopic approach to the sella. In all instances, the pituitary adenomas were noted to be easily dissected from the normal gland. Review of the operative reports did not mention any dural

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invasion or difficulty in achieving an adequate plane of dissection around the adenoma.

The presence of a concurrent pituitary adenoma with a gangliocytoma raises questions regarding the pathogenesis of MGAs. While the exact etiology of MGAs is not well understood, it is clear

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that gangliocytomas are frequently associated with a pituitary adenoma and in the majority of these cases, the concomitant adenoma is a GH secreting adenoma.4,11,13,16,21,23,25,27-29

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Nevertheless, gangliocytomas have also been previously reported in association with prolactin and adrenocorticotrophic hormone secreting adenomas.3,5,6,14,20,22,24-26,29,30 In our series, all but one tumor was a somatotroph adenoma. Of the nine tumors that were immunoreactive for GH, five had biochemical and clinical features of acromegaly and four were silent GH secreting adenomas. Five of the GH-secreting adenomas had focal PRL staining. Whereas 66% of GHstaining adenomas were associated with systemic GH or IGF-1 secretion, none of the patients

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ACCEPTED MANUSCRIPT Shepard with evidence of PRL staining had elevated systemic PRL levels, a finding commonly seen in somatotroph adenomas.32

Although some authors have reported no sex predilection, in our

series 70% of the patients were female.33 This is consistent with the findings of Kurosaki et al.

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who described 6 cases, all of whom were female, and Kontogeorgos who presented 7 cases, of which five were female.16,18

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Table 3 depicts the reported cases of MGAs in the literature.3-30 When those cases are combined with our data, patients with MGA have evidence of a hypersecretory pituitary adenoma in 75%

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of cases. Acromegaly accounts for 54% of MGA cases while Cushing’s disease and prolactinomas account for 11% and 10%, respectively. Gangliocytomas have been reported to contain gonadotropin releasing hormone (GnRH), growth hormone releasing hormone (GHRH), somatostatin, thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH).

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As such, it is not surprising that the presence of gangliocytomas within hypersecretory pituitary adenomas is of pathophysiologic interest with respect to the development of pituitary adenomas. Indeed, some authors suggest that the gangliocytoma induces adenoma formation by endocrine

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or paracrine stimulation via GHRH or CRH.25,26 In prior cases where the gangliocytoma had isolated staining for CRH, all patients have presented with Cushing’s disease with the pituitary

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adenoma staining positive for ACTH.6,25,30 There have been 10 reports of GHRH being secreted by the gangliocytoma component of the MGA, and in all 10 cases, the patients have presented with acromegaly.11,16,18,23,25-27,29 Although circumstantial, this raises the possibility that pituitary adenoma formation may be the result of a hypersecretory gangliocytoma in select cases. On the other hand, not all Cushing’s cases are CRH positive.29 Moreover, pituitary hyperplasia has never been reported in other extrahypothalamic ganglion tumors.15 Thus, some hypothesize that

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ACCEPTED MANUSCRIPT Shepard the co-occurrence is coincidental; that there is a known high prevalence of adenomas in the general population and the gangliocytoma occurs because of abnormal migration of

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hypothalamic neurons during the early phase of embryogenesis.15

A third theory suggests that these mixed tumors may have a common origin or derived from transdifferentiation of neuroendocrine cells into neuronal elements.34,35 Recent studies, including

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one prior investigation examining the pathological nuances of MGAs from some patients

reported herein, suggest that transdifferentiation of neuroendocrine cells into neuronal elements

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is seen in these tumors by histopathological features and the coexpression of the acidophiliclineage transcription factor Pit-1 in both adenomatous and ganglionic cells.34 Thus, the pathogenesis of MGAs remains a subject of debate.

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Our study has several limitations. First, our study is retrospective in manner and is therefore subject to selection or recall bias. Furthermore, clinical and radiographic follow-up was available in only 7 of the 10 patients reported in this study. How the three patients may have

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differed in their long-term outcome could significantly change the outcomes of our study. While other authors may have excluded these patients from analyses, we have included them herein in

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order to better characterize the presentation and associated endocrinopathies that affect patients with MGAs.

Conclusion:

Gangliocytomas of the pituitary are most often associated with a secretory adenoma. Although an associated somatotroph adenoma is most common, lactotroph and corticotroph adenomas

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ACCEPTED MANUSCRIPT Shepard have also been described. Transsphenoidal surgery is tolerated well in patients with these tumors and, in combination with adjuvant radiosurgery and medical therapy, low rates of

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recurrence and reversal of pre-operative endocrinopathy can be expected in most patients.

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Asada H, Otani M, Furuhata S, Inoue H, Toya S, Ogawa Y. Mixed pituitary adenoma and gangliocytoma associated with acromegaly--case report. Neurol Med Chir (Tokyo). 1990;30(8):628-632. Li JY, Racadot O, Kujas M, Kouadri M, Peillon F, Racadot J. Immunocytochemistry of

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Figure 1 - A: Pathologic features of mixed gangliocytoma and somatotroph adenomas are characterized by a combination of adenomatous cells intermixed with ganglionic cells embedded

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in a neuropil-like matrix. B: In these combined tumors, the adenomatous component are

generally composed of sparsely-granulated cells with small, amphophilic cytoplasm and central nucleus; the cells harbor intracytoplasmic fibrous bodies (not shown). C: Immunostaining for

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GH shows focal, but patchy reactivity in the adenomatous cells with no labeling of the

ganglionic cells. D: Ganglionic cells and their cellular processes are strongly immunoreactive for

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neuronal markers including neurofilament protein.

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ACCEPTED MANUSCRIPT Table 1: Baseline characteristics of patients mixed gangliocytoma-adenomas Tumor Size

Hormonal Secretion

Hormonal IHC Stain

Degree of Resection

Surgical Complications

Acromegaly

Macro

GH

GH

Subtotal

None

2*

F

28

Acromegaly

Macro

GH

GH-PRL

GTR

None

3

F

33

Incidental

Micro

None

GH-PRL

GTR

None

4

M

44

Acromegaly

Macro

GH

GH-PRL

GTR

None

5

F

60

Recurrent Cushing’s

Micro

ACTH

ACTH

GTR

None

6*

M

40

Acromegaly

Macro

GH

GH

Subtotal

None

7*

F

52

Incidental

Macro

None

GH

GTR

None

8*

F

44

Incidental

9*

F

63

Incidental

10*

M

38

Acromegaly

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1*

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Presentation

F

Age at Surgery (Yr) 47

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Gender

Macro

GH

GH-PRL

GTR

None

Macro

None

GH, PRL

GTR

None

Macro

GH

GH

Subtotal

CSF Leak

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Case

CSF – Cerebrospinal Fluid; F – Female; GH – Growth Hormone; GTR – Gross total resection; IHC – Immunohistochemistry; Macro – Macroadenoma; M – Male; Micro – Microadenoma; PRL – Prolactin; Yr – year

AC C

EP

* - Clinical follow up available

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Table 2: Patients with clinical and endocrinologic follow-up Age at Surgery (Yr) 47

Acromegaly

Clinical f/u (Mo.) 180

Radiographic f/u (Mo.) 180

Degree Rsxn Subtotal

GKRS

Clinical Improvement Yes

GTR

No

Yes

80

Subtotal

GKRS, pegvisomant

Yes

2

3

GTR

No

n/a

Incidental

74

74

GTR

No

n/a

63

Incidental

13

13

GTR

No

n/a

38

Acromegaly

13

13

Subtotal

Rtx

Yes

Presentation

F

2

F

28

Acromegaly

132

48

6

M

40

Acromegaly

99

7

F

52

Incidental

8

F

44

9

F

10

M

M AN U

1

Adjuvant Tx

RI PT

Gender

SC

Case

AC C

EP

TE D

F/u – follow-up; GKRS – Gama knife radiosurgery; Mo. – Month; n/a – Not applicable; Rsxn – Resection; Rtx –Fractionated radiation; Tx – Treatment; Yr – Year

ACCEPTED MANUSCRIPT Table 3: Previously documented cases of mixed gangliocytoma-adenomas

1 1 1

Clinical Endocrinopathy Cushings Cushings Cushings

ACTH-PRL ACTH-PRL ACTH

Gangliocytoma Component PRL n/a CRH

2

Asymptomatic

n/a

n/a

1 16

n/a GH-PRL; GH

n/a n/a

2

Acromegaly Asymptomatic (4), Acromegaly (8), Prolactinoma (4) Acromegaly

Zhou et al., 2012 Jaiswal et al., 201210

1 1

Asymptomatic Asymptomatic

NFA GH

Sy et al., 201012 Koutourousiou et al., 201013

1 3

Asymptomatic Acromegaly

NFA GH-PRL

Mikami et al., 200815 Serri et al., 200814 Kontogeorgos et al., 200616

1 1 7

Asymptomatic Prolactinoma Acromegaly

PRL PRL GHRH (3)

Hans et al., 200219 Perry et al., 200217 Bodi et al., 200220 Kurosaki et al., 200218

1 1 1 6

Asymptomatic Asymptomatic Prolactinoma Acromegaly

Luna et al., 20014 Geddes et al., 200022

1 8

Acromegaly Asymptomatic (4), Acromegaly (3), Cushings (1) Acromegaly

ACTH-PRL PRL GH-PRL (5), GH (2) GH-PRL GH ACTH-GH-PRL GH-PRL (2), GH (4) GH-PRL GH-PRL (3), ACTH (1), GH (1), Neg (1) GH GH-PRL GH-PRL (2); ACTH (1)

GHRH ACTH (1)

GH-PRL (2), ACTH (1) ACTH GH-PRL

GHRH (2), CRH (1)

Tanriover et al., 2014 Qiao et al., 20143

7

Crowley et al., 201211 9

Sabel et al., 200021

1 23

GHRH n/a n/a n/a n/a

n/a n/a PRL GHRH (5), CRHGHRH (1) n/a n/a

n/a

Puchner et al., 199326 Slowik et al., 199027

1 1

Acromegaly Prolactinoma , Cushings, Asymptomatic Acromegaly (2), Cushings (1) Cushings Acromegaly

Asada et al., 199028

1

Acromeglay

GH

GHRH

4

Acromegaly, Cushings, Prolactinoma, Asymptomatic Cushings

GH (1), PRL (2), ACTH (1)

ACTH-GHRH (1), PRL (1)

ACTH

CRH

Li et al., 1989

29

3

AC C

Saeger et al., 199425

1 3

EP

Morikawa et al., 1997 Towfighi et al., 199624

GH-PRL

RI PT

Chen et al., 20148

SC

Sergeant et al., 201735 Kissiedu et al., 20155 Domingue et al., 20156

Secretory IHC

M AN U

N

TE D

Author & Year

Asa et al., 198430

1

GH GHRH

ACTH - Adrenocorticotropic hormone; CRH - Corticotropin-releasing hormone; GH – Growth Hormone; GHRH – Growth hormone releasing hormone; IHC – Immunohistochemistry; N – Number of cases, n/a – not reported; Neg – Negative, NFA – Non-functioning adenoma; PRL – Prolactin

AC C

EP

TE D

M AN U

SC

RI PT

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Highlights:

AC C

EP

TE D

M AN U

SC

RI PT

-Mixed pituitary gangliocytoma-adenomas (MGAs) are rare tumors of the sella -MGAs are hormonally active and are often associated with growth hormone secretion -Patients with MGAs have low recurrence rates following transphenoidal surgery -Reversal of pre-existing endocrinopathy is feasible in most patients with MGAs

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Disclosures:

AC C

EP

TE D

M AN U

SC

RI PT

The authors report no conflicts of interest and have no financial disclosures.