Management of Cushing's Disease After Failed Surgery - A Review

Abstract:Selective transsphenoidal adenomectomy is generally recommended for initial treatment of Cushing's disease (CD) because it achieves a high (70-85%) rate of remission. However, if initial surgery is not successful, the approach to persistent or recurrent CD is more complex. Because residual or recurrent adenoma is typically found at the site of the original adenoma, repeat transsphenoidal surgery is recommended including selective adenomectomy, hemihypophysectomy or total hypophysectomy. If repeat pituitary surgery does not achieve remission, then possible adjuvant therapies include radiosurgery or stereotactic radiotherapy, bilateral adrenalectomy, and/or medical therapy. In all cases of persistent or recurrent CD, successful treatment requires close collaboration of endocrinologists, radiation oncologists and neurosurgeons.

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Transsphenoidal surgery for Cushing's disease: a review of success rates, remission predictors, management of failed surgery, and Nelson's Syndrome

Neurosurgical FOCUS ◽

10.3171/foc.2007.23.3.7 ◽

2007 ◽

Vol 23 (3) ◽

pp. 1-6 ◽

Cited By ~ 67

Author(s):

Daniel F. Kelly

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Remission Rate ◽

Cushing's Disease ◽

Surgical Morbidity ◽

Nelson’S Syndrome ◽

Nelson's Syndrome ◽

Radio Therapy ◽

Transsphenoidal Adenomectomy

✓ Cushing's disease is a serious endocrinopathy that, if left untreated, is associated with significant morbidity and mortality rates. After diagnostic confirmation of Cushing's disease has been made, transsphenoidal adenomectomy is the treatment of choice. When a transsphenoidal adenomectomy is performed at experienced transsphenoidal surgery centers, long-term remission rates average 80% overall, surgical morbidity is low, and the mortality rate is typically less than 1%. In patients with well-defined noninvasive microadenomas, the long-term remission rate averages 90%. For patients in whom primary surgery fails, treatment options such as bilateral adrenalectomy, stereotactic radiotherapy or radiosurgery, total hypophysectomy, or adrenolytic medical therapy need to be carefully considered, ideally in a multidisciplinary setting. The management of Nelson's Syndrome often requires both transsphenoidal surgery and radio-therapy to gain disease control.

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Repeat transsphenoidal surgery for Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.1989.71.4.0520 ◽

1989 ◽

Vol 71 (4) ◽

pp. 520-527 ◽

Cited By ~ 153

Author(s):

Robert B. Friedman ◽

Edward H. Oldfield ◽

Lynnette K. Nieman ◽

George P. Chrousos ◽

John L. Doppman ◽

...

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Ct Scanning ◽

Pituitary Surgery ◽

Cushing's Disease ◽

Repeat Surgery ◽

Content Type ◽

Preoperative Ct ◽

Pituitary Irradiation ◽

Fine Print

✓ Transsphenoidal resection of adrenocorticotrophic hormone (ACTH)-producing pituitary adenomas has the potential of curing most patients with Cushing's disease. However, transsphenoidal exploration of the pituitary is not always curative, and patients who have remission of hypercortisolism following surgery occasionally develop a recurrence. Whether repeat pituitary surgery should be performed for recurrent or persistent Cushing's disease has not been evaluated previously. To determine the efficacy of transsphenoidal surgery in recurrent or persistent Cushing's disease, we performed transsphenoidal surgery in 31 patients (22 women and nine men) who had previously undergone a transsphenoidal operation and two female patients who had had previous pituitary irradiation only. In 24 (73%) of the 33 patients, remission of hypercortisolism was achieved by surgery. Although preoperative computerized tomography (CT) scanning identified an adenoma in only three of the 33 patients, in 20 patients a discrete adenoma was identified at pituitary exploration. The incidence of remission of hypercortisolism was greatest if an adenoma was identified at surgery and the patient received selective adenomectomy (19, or 95% of 20 patients), if there was evidence at surgery or by preoperative CT scanning that the previous surgical exposure of the pituitary was incomplete (seven, or 78% of nine patients), if an adenoma was seen on preoperative CT scanning (three of three patients), or if the patient had had prior pituitary irradiation without surgery (two of two patients). In contrast, only five (42%) of 12 patients who received subtotal or total hypophysectomy had remission of hypercortisolism. Surgically induced hypopituitarism occurred in six (50%) of these 12 patients, but in only one (5%) of the 20 patients who underwent selective adenomectomy. Three (13%) of the 24 patients who were in remission from hypercortisolism following repeat surgery developed recurrent hypercortisolism 10 to 47 months postoperatively. Repeat transsphenoidal exploration of the pituitary and treatment limited to selective adenomectomy should be considered in patients with hypercortisolism despite previous pituitary treatment. If an adenoma is identified during surgery, the chance of remission of Cushing's disease is high and the risk of hypopituitarism is low; however, if no adenoma can be found and partial or complete hypophysectomy is performed, remission of hypercortisolism is less likely and the risk of hypopituitarism is about 50%.

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SAT-248 Cushing’s Disease with Two ACTH-Producing Pituitary Tumors

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.348 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Christine Mathai ◽

Jonathan Robert Anolik

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Pituitary Tumors ◽

Residual Tumor ◽

Dexamethasone Suppression Test ◽

Cushing's Disease ◽

Initial Surgery ◽

Morning Cortisol ◽

Suppression Test ◽

Dexamethasone Suppression

Abstract Objective: The objective of this case report is to discuss a case of Cushing’s disease with two ACTH-producing pituitary tumors and emphasize consideration of repeat surgery as a treatment modality for unsuccessful initial surgery. Methods: We present a case of a patient with Cushing’s disease with two ACTH-producing pituitary tumors and a literature review. Results: A 36 year-old female found to have left supraclavicular fossa swelling was screened for Cushing’s syndrome. Midnight salivary cortisol levels elevated at 0.636 ug/dL and 0.316 ug/dL (<0.010–0.090 ug/dL). 24-hour urine cortisol 162 ug/24 hr (0–50 ug/24 hr). 1-mg dexamethasone suppression test 14.0 ug/dL. Serum morning cortisol 26.4 ug/dL with corresponding ACTH 66.7 pg/mL (7.2–63.3 pg/mL). MRI brain with and without contrast showed a 7-mm relatively hypoenhancing lesion of the anterior pituitary gland. 8-mg dexamethasone suppression test 2.7 ug/dL. She underwent transsphenoidal surgery (TSS) and pathology was consistent with a pituitary adenoma staining positive for ACTH. No residual tumor was seen. Postoperative morning serum cortisol 17.0 ug/dL and ACTH 79 pg/mL (9–46 pg/mL). She had repeat TSS and the area of resection was clean with no residual tumor but a second adenoma was found that was not visualized on MRI and was distinct from the initial lesion. Postoperative morning cortisol 0.7 ug/dL and ACTH <9 pg/mL (9–46 pg/mL). Pathology was consistent with pituitary adenoma staining positive for ACTH. She is now on steroids for central adrenal insufficiency. Discussion: First-line treatment for Cushing’s disease is surgical resection of the primary lesion (Nieman LK, Biller BMK, et al. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015; 100(8):2807–2831). Remission rates are 73–76% for selectively resected microadenomas but 43% for macroadenomas (Nieman et al. 2015). For patients who undergo a noncurative surgery, second-line therapies include repeat TSS, radiotherapy, medical therapy, and bilateral adrenalectomy. Repeat TSS is recommended particularly in patients who had evidence of incomplete resection or a pituitary lesion on imaging although this was not the case with our patient. Repeat TSS is cited to be successful in about 50–60% of cases (Patil CG, Veeravagu A, et al. Outcomes after repeat transsphenoidal surgery for recurrent Cushing’s disease. Neurosurgery. 2008;63(2):266–270) but carries an increased risk of hypopituitarism and lower likelihood of remission compared to initial surgery. Remission can be achieved more rapidly compared to other second-line treatments. Conclusion: In Cushing’s Disease with unsuccessful initial surgery, consideration for repeat TSS may be considered when there is access to an expert pituitary surgeon.

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Endoscopic Transsphenoidal Pituitary Surgery: Evidence of an Operative Learning Curve

Neurosurgery ◽

10.1227/neu.0b013e3181ef25c5 ◽

2010 ◽

Vol 67 (5) ◽

pp. 1205-1212 ◽

Cited By ~ 70

Author(s):

Paul Leach ◽

Ahmed H Abou-Zeid ◽

Tara Kearney ◽

Julian Davis ◽

Peter J Trainer ◽

...

Keyword(s):

Learning Curve ◽

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Length Of Hospital Stay ◽

Visual Outcome ◽

Pituitary Surgery ◽

Cushing's Disease ◽

Pituitary Fossa ◽

Duration Of Surgery ◽

Time Periods

Abstract BACKGROUND: The use of the fiberoptic endoscope is a recent innovation in pituitary surgery. OBJECTIVE: To investigate the evidence of an operative learning curve after the introduction of endoscopic transsphenoidal surgery in our unit. METHODS: The first 125 patients who underwent endoscopic transnasal transsphenoidal surgery for pituitary fossa lesions between 2005 and 2007 performed by 1 surgeon were studied. Changes in a number of parameters were assessed between 2 equal 15-month time periods: period 1 (53 patients) and period 2 (72 patients). RESULTS: There were 67 patients (54%) with nonfunctioning adenomas, 22 (18%) with acromegaly, and 10 (8%) with Cushing's disease. Between study periods 1 and 2, there was a decrease in the mean duration of surgery for nonfunctioning adenomas (from 120 minutes to 91 minutes; P < .01). This learning effect was not apparent for functioning adenomas, the surgery for which also took longer to perform. The proportion of patients with an improvement in their preoperative visual field deficits increased over the study period (from 80% to 93%; P < .05). There were nonsignificant trends toward improved endocrine remission rates for patients with Cushing's disease (from 50% to 83%), but operative complications, notably the rates of hypopituitarism, did not change. Overall length of hospital stay decreased between time periods 1 and 2 (from 7 to 4 days median; P < .01). CONCLUSION: The improvements in the duration of surgery and visual outcome noted after about 50 endoscopic procedures would favor the existence of an operative learning curve for these parameters. This further highlights the benefits of subspecialization in pituitary surgery.

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Delayed Remission after Transsphenoidal Surgery in Patients with Cushing’s Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1672 ◽

2010 ◽

Vol 95 (2) ◽

pp. 601-610 ◽

Cited By ~ 81

Author(s):

Elena Valassi ◽

Beverly M. K. Biller ◽

Brooke Swearingen ◽

Francesca Pecori Giraldi ◽

Marco Losa ◽

...

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Tertiary Care ◽

Case Series ◽

Expectant Management ◽

Pituitary Surgery ◽

Cushing's Disease ◽

Optimal Timing ◽

Retrospective Case

Abstract Background: Transsphenoidal surgery (TSS) is the treatment of choice for Cushing’s disease (CD). Postoperative hypercortisolemia mandates further therapy. Objective: The aim of the study was to characterize patients without immediate postoperative remission who have a delayed decrease to normal or low cortisol levels without further therapy. Design and Setting: A retrospective case series was conducted at three tertiary care centers. Patients and Intervention: We reviewed the records of 620 patients (512 females, 108 males; mean age, 38 ± 13 yr) who underwent transsphenoidal pituitary surgery for CD between 1982 and 2007. Results: Outcomes were classified into the following three groups based upon the postoperative pattern of cortisol testing: group IC (immediate control) included 437 of the 620 patients (70.5%) with hypocortisolism and/or cortisol normalization throughout the postoperative follow-up; group NC (no control) included 148 of 620 patients (23.9%) with persistent hypercortisolism; and group DC (delayed control) included 35 of 620 patients (5.6%) who had early elevated or normal UFC levels and developed a delayed and persistent cortisol decrease after an average of 38 ± 50 postoperative days. The total rate of recurrence was 13% at a median follow-up time of 66 months after TSS; the cumulative rate of recurrence at 4.5 yr was significantly higher in group DC vs. group IC (43 vs. 14%; P = 0.02). Conclusions: Hormonal assessment in the immediate postoperative period after TSS for CD may be misleading because delayed remission can occur in a subset of patients. Expectant management and retesting may spare some patients from unnecessary further treatment. Optimal timing to determine the need for further therapy after TSS remains to be determined.

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Transsphenoidal pituitary surgery via the endoscopic technique: results in 35 consecutive patients with Cushing’s disease

Acta Endocrinologica ◽

10.1530/eje.1.02133 ◽

2006 ◽

Vol 154 (5) ◽

pp. 675-684 ◽

Cited By ~ 63

Author(s):

R T Netea-Maier ◽

E J van Lindert ◽

M den Heijer ◽

A van der Eerden ◽

G F F M Pieters ◽

...

Keyword(s):

Cushing’S Disease ◽

Remission Rate ◽

Clinical Signs ◽

Pituitary Surgery ◽

Endoscopic Technique ◽

Cushing's Disease ◽

Cerebrospinal Fluid Leakage ◽

Failure Group ◽

Initial Surgery ◽

Transsphenoidal Pituitary Surgery

Objective and design: The endoscopic technique has been recently introduced in the field of transsphenoidal pituitary surgery. This technique allows inspection of sellar, supra- and parasellar structures and removal of the tumor under direct visualization, is minimally traumatic and permits easier reoperations. This is the first report on the results of endoscopic surgery for patients with Cushing’s disease. Our aim was to retrospectively analyze the results of pituitary surgery in 35 consecutive patients with Cushing’s disease operated in our hospital after the introduction of the endoscopic technique (1998–2004). Methods: Remission was defined as suppression of plasma cortisol (≤50 nmol/L) after 1 mg dexamethasone overnight determined in the first 3 months after surgery and disappearance of clinical signs and symptoms of hypercortisolism. The patients were followed for an average of 27 months (range 4 to 81 months, median 20 months). Results: Pituitary MRI showed a macroadenoma in 6 patients, a microadenoma in 17 patients and no adenoma in 12 patients. After the initial surgery 27 patients (77%) were in remission. None of the patients had a relapse during follow-up. In the remaining 8 patients hypercortisolemia persisted after surgery. Three of them had a second endoscopic pituitary surgery resulting in remission in two patients. In one patient a second endoscopic pituitary surgery will soon follow. The remaining four patients were treated with radiotherapy postoperatively. Two of them were at the time of data collection in remission. One patient from the remission group had a serious epistaxis and three patients had cerebrospinal fluid leakage, one requiring an external lumbar drain, shortly after surgery. No complications were recorded in the failure group. Postoperatively 34% of all patients required substitution with levothyroxine, 40% required substitution with glucocorticoids, 17% received estrogens or testosterone and 6% still required desmopressin. Conclusions: Endoscopic transsphenoidal pituitary surgery resulted in our series of patients with Cushings disease in an excellent postoperative remission rate. A randomized clinical trial, comparing endoscopic and conventional pituitary surgery in patients with Cushings disease, is needed to determine the pros and cons of both techniques.

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Early repeat surgery for persistent Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.1994.80.1.0037 ◽

1994 ◽

Vol 80 (1) ◽

pp. 37-45 ◽

Cited By ~ 135

Author(s):

Zvi Ram ◽

Lynnette K. Nieman ◽

Gordon B. Cutler ◽

George P. Chrousos ◽

John L. Doppman ◽

...

Keyword(s):

Cortisol Level ◽

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Cushing's Disease ◽

Sustained Remission ◽

Repeat Surgery ◽

Content Type ◽

Initial Surgery ◽

Early Reoperation ◽

Fine Print

✓ The potential efficacy of early repeat transsphenoidal surgery for persistent Cushing's disease has not previously been examined. On 222 patients with no prior pituitary treatment and a preoperative diagnosis of Cushing's disease, 29 (13%) remained hypercortisolemic after an initial transsphenoidal pituitary exploration. Seventeen of these 29 patients underwent further surgery 7 to 46 days after the initial transsphenoidal approach in order to completely excise suspected residual tumor. Patients were followed for 4 to 84 months (mean ± standard deviation, 34 ± 25 months) to document sustained remission or recurrence of Cushing's disease (a urine free cortisol level > 90 µg/day was considered evidence of recurrence). Of the 17 patients with repeat surgery, 12 (71%) had resolution of hypercortisolism (morning plasma cortisol level < 5 µg/dl); however, in three of these 12, hypercortisolism recurred 5, 12, and 24 months later. In 14 patients a lesion that appeared to be a tumor was identified during the initial procedure or on histological examination. Of these, 12 had immediate resolution of hypercortisolism and nine are still in remission. Three patients, in whom no adenoma could be identified during the initial surgery or an examination of the partial hypophysectomy specimen from the initial surgery, had persistent Cushing's syndrome after the second operation. Seven (41%) of the 17 patients developed hypopituitarism requiring treatment with thyroid hormone, gonadal steroid, or vasopressin replacement. The low incidence of identification of an adenoma on computerized tomography or magnetic resonance images (three of 17 patients), the failure to find a corticotrophic adenoma during the initial surgery (10 of 17 patients), and the failure of these 17 patients to respond to the initial transsphenoidal surgery suggest that they may comprise a subset of patients who are more difficult to treat successfully with surgery than most patients with Cushing's disease. Despite that, early reoperation induced immediate remission of hypercortisolism in 71% of cases, but did so at the expense of a high risk of hypopituitarism. However, since the alternative treatments (such as radiation therapy, long-term drug therapy, or bilateral adrenalectomy) also have potential adverse effects, early reoperation deserves consideration for the management of persistent Cushing's disease, especially when an adrenocorticotrophic hormone-secreting adenoma was partially excised during the first surgery.

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Persistent Cushing’s Disease after Transsphenoidal Surgery: Challenges and Solutions

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1220-6056 ◽

2020 ◽

Author(s):

Adriana Albani ◽

Marily Theodoropoulou

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Tumor Resection ◽

Pituitary Surgery ◽

Primary Treatment ◽

Cushing's Disease ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Mortality And Morbidity ◽

Surgical Failure

AbstractTranssphenoidal surgery remains the primary treatment for Cushing’s disease (CD). However, despite the vast improvements in pituitary surgery, successful treatment of CD remains a great challenge. Although selective transsphenoidal removal of the pituitary tumor is a safe and effective procedure, the disease persists in around 22% of CD patients due to incomplete tumor resection. The persistence of hypercortisolism after pituitary surgery may also be the consequence of a misdiagnosis, as can occur in case of ectopic ACTH secretion or pseudo-Cushing. Considering the elevated mortality and morbidity characterizing the disease, a multidisciplinary approach is needed to minimize potential pitfalls occurring during the diagnosis, avoid surgical failure and provide the best care in those patients who have undergone unsuccessful surgery. In this review, we analyze the factors that could predict remission or persistence of CD after pituitary surgery and revise the therapeutic options in case of surgical failure.

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Surgery for Cushing’s disease in pregnancy: our experience and a literature review

Annals of The Royal College of Surgeons of England ◽

10.1308/rcsann.2018.0175 ◽

2019 ◽

Vol 101 (1) ◽

pp. e26-e31 ◽

Cited By ~ 3

Author(s):

K Jolly ◽

A Darr ◽

W Arlt ◽

S Ahmed ◽

N Karavitaki

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Cushing’S Syndrome ◽

Diaphragmatic Hernia ◽

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Antenatal Clinic ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Transsphenoidal Adenomectomy ◽

In Pregnancy

Cushing’s syndrome in pregnancy is a rare phenomenon and there is limited literature on its management. Cushing’s disease in pregnancy is even less common and there is little guidance to help in the treatment for this patient group. Diagnosis of Cushing’s syndrome in pregnancy is often delayed due to overlap of symptoms. In addition, there are no validated diagnostic tests or parameters documented. We present a case of a 30-year-old woman presenting to the antenatal clinic at 13 weeks of pregnancy with high suspicion of Cushing’s disease. Her 21-week fetal scan showed a congenital diaphragmatic hernia and she underwent pituitary magnetic resonance imaging, which confirm Cushing’s disease. She successfully underwent transsphenoidal adenomectomy with histology confirming a corticotroph adenoma. Tests following transsphenoidal surgery confirmed remission of Cushing’s disease and she underwent an emergency caesarean section at 38 weeks. Unfortunately, her baby died from complications associated with the congenital abnormality 36 hours after birth. The patient remains in remission following delivery. To date, there have been no reported cases of congenital diaphragmatic hernia associated with Cushing’s disease in pregnancy. In addition, we believe that this is only the eighth reported patient to have undergone successful transsphenoidal surgery for Cushing’s disease in pregnancy.

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Sinonasal Outcomes after Pituitary Surgery in Patient's with Cushing's Disease

10.1055/s-0040-1702408 ◽

2020 ◽

Author(s):

Nadeem R. Kolia ◽

Paul A. Gardner ◽

Carl H. Snyderman ◽

Eric W. Wang

Keyword(s):

Cushing’S Disease ◽

Pituitary Surgery ◽

Cushing's Disease

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