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Table of Contents    
Year : 2020  |  Volume : 68  |  Issue : 2  |  Page : 403-406

Efficacy of Endoscopic Transsphenoidal Surgery for Cushing's Disease: Case Series and Review of the Literature

1 Department of Neurosurgery, Nara Prefecture General Medical Center, Nara; Department of Neurosurgery, Nara Medical University, Kashihara, Japan
2 Department of Neurosurgery, Nara Medical University, Kashihara, Japan
3 Department of Neurosurgery, Osaka Police Hospital, Osaka, Japan

Date of Web Publication15-May-2020

Correspondence Address:
Daisuke Wajima
Shijo-cho 840, Kashihara, Nara 634-8522
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.284363

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 » Abstract 

Background: This study was performed to examine the efficacy of endoscopic transsphenoidal surgery (ETS) for Cushing's disease at a single institute and to review past reports.
Material and Methods: We studied eight consecutive patients who underwent ETS for Cushing's disease. The radiological evaluation comprised a detailed examination of preoperative magnetic resonance images (MRIs), including inferior petrosal sinus sampling, for cases with normal renal function. Remission was evaluated at least three months after surgery and was defined by the presence of hypocortisolemia that required steroid replacement therapy or eucortisolemia with suppression to <1.8 μg/dL after 1mg of dexamethasone.
Results: In all cases preoperative MRI was abnormal and included two macroadenomas (25 %). Pathological confirmation of an adenoma was possible in all patients. The mean follow-up period was 5.6 (2–7) years. Remission was confirmed in 75.0% of the cases and was higher in rate for microadenoma (100%) than for macroadenoma (50%). Postoperatively , no cerebrospinal fluid rhinorrhea occurred, but new endocrine deficits were noted in 25% of patients.
Conclusion: Based on this study, ETS enhanced the intrasellar identification of adenomatous tissue, which led to low remission and complication rates that were comparable with those of traditional microsurgery for Cushing's disease.

Keywords: Cushing's disease, endoscopic transsphenoidal surgery, pituitary adenoma, remission
Key Message: ETS enhanced the intrasellar identification of adenomatous tissue, which led to low remission and complication rates that were comparable with those of traditional microsurgery for Cushing's disease.

How to cite this article:
Masui K, Wajima D, Aketa S, Nishimura F. Efficacy of Endoscopic Transsphenoidal Surgery for Cushing's Disease: Case Series and Review of the Literature. Neurol India 2020;68:403-6

How to cite this URL:
Masui K, Wajima D, Aketa S, Nishimura F. Efficacy of Endoscopic Transsphenoidal Surgery for Cushing's Disease: Case Series and Review of the Literature. Neurol India [serial online] 2020 [cited 2022 Aug 18];68:403-6. Available from: https://www.neurologyindia.com/text.asp?2020/68/2/403/284363

The outcomes of transsphenoidal surgery for Cushing's disease has been satisfactory and led to remission in 70%–90% of patients.[1],[2] However, the literature on the outcomes specific to endoscopic transsphenoidal surgery (ETS) is relatively sparse. Nevertheless, persistent hypercortisolism and recurrent disease continue to be limitations of surgery for Cushing's disease, necessitating repeat or salvage interventions in approximately 5%–25% of cases.[3] The objective of this study was to describe the outcomes of our initial experiences of ETS for Cushing's disease at a single institute and to review past reports.

 » Materials and Methods Top

This study included eight consecutive patients who underwent ETS for Cushing's disease at our institution between January 2009 and December 2014. Institutional review board approval was obtained for the purposes of this study. The mean follow-up period was 5.6 (2–7) years.

The diagnosis of Cushing's disease was suspected when the following were present: (1) elevated 24-h urinary-free cortisol at >100 μg, (2) failure to suppress serum cortisol to undetectable levels with low-dose dexamethasone, and (3) loss of circadian rhythm of cortisol production, which manifested as cortisol >1.8 μg/dL or adrenocorticotropic hormone (ACTH) >7.5 pg/mL on midnight sampling.[4],[5] In patients with two or more positive screening tests, suppression of basal cortisol to <50% with high-dose (8 mg) dexamethasone was considered indicative of Cushing's disease. If the clinical and hormonal profile suggested Cushing's disease, the patients were subjected to magnetic resonance imaging (MRI) of the brain. When microadenoma was suspected by MRI, cavernous sinus (CS) venous sampling through the inferior petrosal sinus was performed in selected cases without renal failure.

Our surgical strategy involved an endoscopic endonasal transsphenoidal pituitary exploration of all patients with biochemically established Cushing's disease, with consideration of the results of preoperative MRI and CS venous sampling. The core principles included attempt for gross total resection of all adenomas, resection of invasive adenomas with angled endoscopes, en bloc excision of microadenoma or macroadenoma based on the margin of pseudocapsule, and piecemeal resection if en bloc resection was difficult. Each tissue sample resected was fixed in 10% buffered formalin and embedded in paraffin. Histological examination included standard hematoxylin–eosin staining; disruption of the acinar architecture with the presence of monomorphic cells was taken as evidence of tumor. Detailed immunohistochemical analyses for ACTH (1:150; Biogenex, San Ramon, CA, USA) and all other anterior pituitary hormones were performed on all 5-μm sections of surgical specimens. Periodic acid-Schiff and cytokeratin stains were also used to confirm Crooke's hyaline change.

No perioperative steroids were administered to facilitate the early evaluation of remission. Venous blood samples for cortisol were drawn 6 h postoperatively and subsequently at 8:00 AM and 8:00 PM on the first seven postoperative days. Random cortisol values were drawn if patients demonstrated signs and symptoms of hypocortisolemia. Patients with a cortisol level <5 μg/dL were started on immediate intravenous steroid replacement with 25 mg hydrocortisone, which was administered at 6-h intervals. Once clinically stable, these patients were subsequently discharged on oral prednisolone. While in the hospital steroid replacement therapy was discontinued for 72 h to reassess the adrenal status. Patients with a basal cortisol >5 μg/dL underwent overnight suppression with 1 mg dexamethasone. Remission was defined by the presence of hypocortisolemia (basal cortisol <5 μg/dL with a requirement for steroid replacement therapy) or eucortisolemia (basal cortisol >5 μg/dL but with suppression to <1.8 μg/dL with dexamethasone).

 » Results Top

The mean age of the cohort was 45.63 years; six patients were women (75%). The mean duration of symptoms before the diagnosis of Cushing's disease was 11.8 months, and the major symptoms included general fatigue, obesity, hyperpigmentation, proximal myopathy, and menstrual irregularities with hirsutism in women. Most patients were either diabetic (75%) or hypertensive (87.5%). One patient had undergone prior microscopic transsphenoidal surgery elsewhere and presented with recurrent Cushing's disease. The clinical and imaging details of the eight patients are summarized in [Table 1], and a summary of the comparisons of our results with those of past reports is shown in [Table 2].
Table 1: Demography and Outcome of the Patients Who underwent ETS for Cushing Disease.

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Table 2: Comparison of Demography and Outcome of the Patients Who underwent ETS for Cushing Disease to th Past Reports.

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In all patients in our series, microadenomas or macroadenomas were suspected on preoperative MRI [Figure 1]a and [Figure 1]b. Inferior petrosal venous sampling was performed in six cases to identify the location of the microadenoma that was causing Cushing's disease. The surgeon's assessment of the number of cases that underwent total resection was 75%. Overall, an adenoma was identified with a single ETS in six patients (75%). En bloc resection was performed in cases of microadenoma, dissecting pseudocapsule membrane, and normal tissue membrane [Figure 1]c. MRI was performed in all cases to confirm postoperative status [Figure 1]d and [Figure 1]e.
Figure 1: MRI images in a patient suspected to have Cushing's disease. A small adenoma is detected on T2-weighted imaging (a, red arrow) and gadolinium-enhanced T1-weighted imaging (b, yellow arrow). An adenoma is detected intraoperatively and en bloc total resection was performed (c). Total resection of the adenoma is confirmed on postoperative T2-weighted imaging (d) and gadolinium-enhanced T1-weighted imaging (e). MRI, magnetic resonance imaging

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All the surgical specimens in this series were adequate for histopathological examination; the presence of monomorphic cells with a disrupted reticulin framework was consistent with a pituitary adenoma [Figure 2]a. A definite ACTH-producing adenoma [Figure 2]b was found in all cases, including one Crooke's cell adenoma [Figure 2]c and [Figure 2]d, as confirmed by positive ACTH immunostaining.
Figure 2: Resected adenoma specimen in a typical (adrenocorticotropic hormone) ACTH-producing adenoma. (a) There are monomorphic cells with a disrupted reticulin framework, findings that were consistent with pituitary adenoma (hematoxylin–eosin staining, 400×). (b) A definite ACTH-producing adenoma is confirmed on immunostaining. Crooke's cell adenoma is confirmed on (c) hematoxylin–eosin staining (400×) and (d) anti-cytokeratin (CAM 5.2) immunostaining (400×)

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Of the eight patients who underwent ETS, four cases (50%) developed intraoperative cerebrospinal fluid (CSF) leakage that required packing of the sella, but there were no cases that developed CSF rhinorrhea postoperatively. Transient diabetes insipidus (DI) was observed in two patients. Overall, one patient required another treatment aside from steroid replacement for at least one new postoperative endocrine deficit detected on the last follow-up.

Overall, remission was achieved in six patients (75%) and was superior in rate for microadenoma (100%) than for macroadenoma (50%). One patient remained in non-remission on follow-up, whereas two patients underwent adjuvant radiation therapy.

 » Discussion Top

In this series, immediate postoperative hypocortisolism was induced surgically in 75% and resulted in an overall remission rate of 75%, when confirmed with a suppression test during remote follow-up. Our results were comparable with those of other reports on the efficacy of ETS for Cushing's disease [Table 1][6],[7],[8],[9],[10]; in all reports, including ours, the overall remission rate was in the range of 70%–90%. A recent report stated that compared with microscopic transsphenoidal surgery, ETS for Cushing's disease had similar remission rates at 70.6%,[11] confirming the efficacy of the latter. In our series, no patients needed repeat operation, but two patients needed adjuvant radiation therapy because of incomplete resection of the tumor. In past reports, including our study, adjuvant therapy was needed in 10%–25% of cases. Our results indicated that patients with an early nadir of postoperative cortisol at <2 μg/dL were several times more likely to achieve remission than patients with late nadir of postoperative cortisol. Immediate induction of hypocortisolemia in the postoperative period has been known to correlate with both remission and a lower risk of recurrence in a number of studies,[12] and the nadir cortisol level after a successful adenomectomy is usually achieved within 72 h after surgery.

Although the sensitivity of conventional MRI has been described as suboptimal in patients with Cushing's disease,[13] we believe that in cases of microadenoma, CS venous sampling is useful to detect the laterality of the tumor and to confirm its pathology. In cases of undetected adenoma on MRI, transsphenoidal exploration may be ineffective, and whole-body positron emission tomography investigation for ectopic ACTH-producing adenoma may be needed.

Transsphenoidal surgery provides a minimally invasive and direct trajectory to pituitary fossa; moreover, the use of angled endoscopes allows resection of extrasellar tumors under direct vision, in contrast to microsurgery, which uses blind curettage and tumor traction. However, the two approaches may be equivalent with regard to the technique for Cushing's disease, which has the distinguishing feature of a high prevalence of microadenoma confined to the sella. Nevertheless, in this study, the remission rate was inferior for macroadenoma compared with microadenoma, a fact that has been noted by other reports on outcomes with larger tumors.[14] These findings suggested that regardless of the technique, extensive tumors are inherently difficult to cure. Notably, the intrasellar illumination provided by the endoscope was reported to be extremely helpful in the intraoperative identification of abnormal tissue.[15]

After transsphenoidal surgery for Cushing's disease, a new deficiency of at least one pituitary hormone has been noted in 10%–30% of patients, and up to 15% of patients can suffer permanent DI.[16] With regard to these complications, our results were comparable with those of the other reports. In our cases, intraoperative CSF leakage was not observed, but the incidence of meningitis and postoperative CSF rhinorrhea was similar to those mentioned by several previous reports.[17] Severe epistaxis, which complicates approximately 3% of transsphenoidal procedures for Cushing's disease,[18] did not occur in our cases. Our study was limited by its retrospective nature and the smaller number of cases, in comparison to that of past reports.

 » Conclusion Top

ETS provided remission in approximately 90% of cases in our case series. The surgical endoscope provided excellent intrasellar illumination that allowed easier tumor identification and, consequently a high rate of pathological confirmation and preservation of normal gland functions postoperatively.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Acebes J, Martino J, Masuet C, Montanya E, Soler J. Early post-operative ACTH and cortisol as predictors of remission in Cushing's disease. Acta Neurochir (Wien) 2007;149:471-9.  Back to cited text no. 1
Barbetta L, Dall'Asta C, Tomei G, Locatelli M, Giovanelli M, Ambrosi B. Assessment of cure and recurrence after pituitary surgery for Cushing's disease. Acta Neurochir (Wien) 2001;143:477-82.  Back to cited text no. 2
Chen JC, Amar AP, Choi S, Singer P, Couldwell WT, Weiss MH. Transsphenoidal microsurgical treatment of Cushing disease: Postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. J Neurosurg 2003;98:967-73.  Back to cited text no. 3
John M, Lila AR, Bandgar T, Menon PS, Shah NS. Diagnostic efficacy of midnight cortisol and midnight ACTH in the diagnosis and localisation of Cushing's syndrome. Pituitary 2010;13:48-53.  Back to cited text no. 4
Kakade HR, Kasaliwal R, Khadilkar KS, Jadhav S, Bukan A, Khare S, et al. Clinical, biochemical and imaging characteristics of Cushing's macroadenomas and their long-term treatment outcome. Clin Endocrinol (Oxf) 2014;81:336-42.  Back to cited text no. 5
Kuo CH, Yen YS, Wu JC, Chen YC, Huang WC, Cheng H. Primary endoscopic trans-nasal trans-sphenoidal surgery for magnetic resonance image-positive Cushing disease: Outcomes of a series over 14 years. World Neurosurg 2015;84:772-9.  Back to cited text no. 6
Wagenmakers M, Boogaarts H, Roerink S, Timmers H, Stikkelbroeck N, Smit J, et al. Endoscopic trans-sphenoidal pituitary surgery: A good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas. Eur J Endocrinol 2013;169:329-37.  Back to cited text no. 7
Dehdashti AR, Gentili F. Current state of the art in the diagnosis and surgical treatment of Cushing disease: Early experience with a purely endoscopic endonasal technique. Neurosurg Focus 2007;23:1-8.  Back to cited text no. 8
Starke RM, Reames DL, Chen CJ, Laws ER, Jane JA Jr. Endoscopic trans-sphenoidal surgery for Cushing disease: Techniques, outcomes, and predictors of remission. Neurosurgery 2013;72:240-7.  Back to cited text no. 9
Pettersen RJ, Halvorsen H, Evang JA, Rønning P, Hol PK, Bollerslev J, et al. Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing's disease. BMC Endocr Disord 2015;15:62.  Back to cited text no. 10
Shirvani M, Motiei-Langroudi R, Sadeghian H. Outcome of microscopic transsphenoidal surgery in Cushing disease: A case series of 96 patients. World Neurosurg 2016;87:170-5.  Back to cited text no. 11
Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Müller OA, Fahlbusch R. Long-term results after microsurgery for Cushing disease: Experience with 426 primary operations over 35 years. J Neurosurg 2008;108:9-18.  Back to cited text no. 12
Bochicchio D, Losa M, Buchfelder M. Factors influencing the immediate and late outcome of Cushing's disease treated by trans-sphenoidal surgery: A retrospective study by the European Cushing's Disease Survey Group. J Clin Endocrinol Metab 1995;80:3114-20.  Back to cited text no. 13
Kakade HR, Kasaliwal R, Khadilkar KS, Jadhav S, Bukan A, Khare S, et al. Clinical, biochemical and imaging characteristics of Cushing's macroadenomas and their long-term treatment outcome. Clin Endocrinol (Oxf) 2014;81:336-42.  Back to cited text no. 14
Jagannathan J, Sheehan JP, Jane JA Jr. Evaluation and management of Cushing syndrome in cases of negative sellar magnetic resonance imaging. Neurosurg Focus 2007;23:1-7.  Back to cited text no. 15
Hammer GD, Tyrrell JB, Lamborn KR, Applebury CB, Hannegan ET, Bell S, et al. Trans-sphenoidal microsurgery for Cushing's disease: Initial outcome and long-term results. J Clin Endocrinol Metab 2004;89:6348-57.  Back to cited text no. 16
Ciric I, Zhao J-C, Du H, Findling JW, Molitch ME, Weiss RE, et al. Trans-sphenoidal surgery for Cushing disease: Experience with 136 patients. Neurosurgery 2012;70:70-81.  Back to cited text no. 17
Semple PL, Laws ER Jr. Complications in a contemporary series of patients who underwent trans-sphenoidal surgery for Cushing's disease. J Neurosurg 1999;91:175-9.  Back to cited text no. 18


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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