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Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation

Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Jan 2024.
This topic last updated: Nov 28, 2023.

INTRODUCTION — Cushing disease is caused by pituitary corticotropin (ACTH)-secreting tumors. These tumors are almost always benign and are usually microadenomas (ie, <10 mm in diameter). In 30 to 40 percent, the microadenoma is so small that it is not detectable by magnetic resonance imaging (MRI), while in 10 to 15 percent a macroadenoma is present. Treatment is aimed first at the anterior pituitary gland.

The progressive stages of treatment that may be required to cure a patient of Cushing disease are shown in the figure (algorithm 1). Primary therapy consists of transsphenoidal surgery or pituitary irradiation. Patients who fail this first approach can be treated either by repeat transsphenoidal surgery, medical therapy, radiotherapy, or, as a final resort, surgical or medical adrenalectomy. An overview of transsphenoidal surgery and pituitary irradiation for the primary therapy of Cushing disease will be reviewed here. An overview of the management of Cushing syndrome, as well as medical therapy and surgical adrenalectomy for Cushing are reviewed separately. (See "Overview of the treatment of Cushing syndrome" and "Medical therapy of hypercortisolism (Cushing's syndrome)" and "Persistent or recurrent Cushing disease: Surgical adrenalectomy".)

TRANSSPHENOIDAL SURGERY — For patients who have corticotroph micro- or macroadenomas, we recommend transsphenoidal surgery as initial treatment. When successful, the patient is cured and is eventually left with normal hypothalamic-pituitary-adrenal function [1,2]. Surgical techniques and results of transsphenoidal surgery for pituitary adenomas are also reviewed in a separate topic. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Corticotroph adenomas'.)

Magnetic resonance imaging (MRI) is performed preoperatively to try to locate the pituitary tumor. However, surgery should be performed even if a tumor is not visualized.

Approach — The operative approach varies. Traditionally, the procedure involved transsphenoidal exploration through either a sublabial or endonasal approach, followed by use of a high-powered microscope that allowed for binocular vision. More recently, use of an endoscope, which does not provide binocular vision, has been advocated but has not been definitively shown to be superior [3]. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Comparison of microscopic versus endoscopic techniques'.)

Extent of surgery — The extent of surgery varies. Ideally, the entire tumor is removed while normal pituitary tissue is left behind. However, in adult patients in whom a microadenoma cannot be identified at the time of surgery and for whom fertility is not an issue, 80 to 90 percent of the pituitary should be resected, leaving a small island attached to the stalk. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Determination of the extent of resection'.)

Preoperative localization — In general, tumors are localized by the preoperative MRI scan or by intraoperative exploration and observation by the surgeon.

MRI — The decision to operate should not depend upon radiographic demonstration of the tumor. High-resolution, contrast-enhanced, thin-section computed tomography (CT) scans detect only approximately one-third of the microadenomas, which appear hypodense after contrast injection (image 1) [4-6]. Because CT scans define bony structures better, the neurosurgeon may, on occasion, request them. (See "Establishing the cause of Cushing syndrome", section on 'Pituitary MRI'.)

Coronal projections of high-resolution MRI at 1.5 T with gadolinium enhancement reveal microadenomas in approximately 60 percent of patients and have replaced CT for localization (image 2 and image 3) [6,7]. In one report, a modified technique known as "spoiled gradient recalled acquisition technique" had superior sensitivity compared with conventional, post-contrast, spin-echo technique (80 versus 49 percent, respectively) but a higher false positive rate (4 versus 2 percent) [8]. False-positive MRI scans can be obtained in 10 percent of subjects with no endocrine disorders [9], who may or may not have "nonfunctioning" microadenomas [10]. False negative scans can occur in patients with an empty sella [11]. Some microadenomas that cannot be visualized with preoperative MRI can be identified using intraoperative ultrasonography [12].

The preoperative radiographic demonstration of tumor improved the likelihood of cure in some but not all centers; other possible confounding factors such as technical experience might account for the differences:

In one retrospective analysis of 54 patients with Cushing disease (26 with pituitary microadenoma on preoperative MRI and 28 with a normal MRI but confirmed pituitary origin of corticotropin [ACTH] secretion on bilateral petrosal sinus sampling), clinical outcome of transsphenoidal surgery was similar regardless of the preoperative MRI findings [13]. Early surgical success rates were 78 and 88 percent in the normal and abnormal MRI groups, respectively: a difference that was not statistically significant.

In a second study of 167 patients with clear-cut microadenoma on MRI, 148 of 167 (88 percent) achieved remission, suggesting that imaging localization may improve outcome [14].

In a third study, 183 of 185 (99 percent) with microadenomas on MRI had initial remission [15].

Inferior petrosal sinus sampling — Measurement of ACTH gradients between the two sinuses during inferior petrosal venous sinus catheterization predicts the correct side of the pituitary tumor in 69 to 80 percent of patients with lateral tumors [16-18]. In the absence of a lesion on MRI, the gradient may be used to choose the side for initial exploration, but if no tumor is found, the other side must be explored. The role of inferior petrosal sinus sampling for localization is reviewed in detail separately. (See "Establishing the cause of Cushing syndrome", section on 'Petrosal venous sinus catheterization'.)

Perioperative glucocorticoids

Before surgery – Preoperative glucocorticoid replacement is not necessary unless cortisol production has been blocked completely by adrenal enzyme inhibitors. In this instance, the patient should be treated like a patient with adrenal insufficiency. (See "Treatment of adrenal insufficiency in adults".)

Practice patterns are variable. Some surgeons do not administer glucocorticoids [19], while others give higher than normal glucocorticoid replacement intraoperatively and for one to three days postoperatively to avoid symptoms and signs of acute steroid withdrawal [20]. There have been no comparisons of the benefits of one or the other approach. One typical regimen is dexamethasone 0.5 mg every six hours for four doses only, eg, only 24 hours of glucocorticoid therapy.

Perioperative glucocorticoid therapy entails virtually no risk for the patient.

After surgery Glucocorticoids must be stopped for 24 hours before serum cortisol can be measured to assess cure. Glucocorticoid replacement can be held for a few days, with careful observation for the development of adrenal insufficiency.

Patients who meet the criteria for successful surgery are hypocortisolemic for up to 12 months after microadenomectomy and require glucocorticoid replacement therapy, which must be supplemented during stress. (See "Treatment of adrenal insufficiency in adults".)

Occasional patients become anorectic and have generalized malaise and postural hypotension three or four days after surgery. These problems often respond to higher doses of glucocorticoid for several days.

Other rare patients with longstanding, severe Cushing disease have such severe symptoms of glucocorticoid withdrawal that replacement doses of glucocorticoid are inadequate, and they temporarily require higher doses, up to twofold higher. Both clinician and patient must recognize that administration of such doses constitutes iatrogenic hypercortisolism. Every effort should be made to taper to a replacement dose, ideally within a few weeks.

Surgical complications

Arginine vasopressin deficiency — Transient, arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) is common and was reported at a rate of 22 percent in a single institution with a high volume of pituitary surgery [21]. In contrast, permanent AVP-D occurs in only a few percent of patients, even among those who have subtotal resection of the gland, although more extensive resection may increase the incidence of permanent AVP-D to as much as 25 percent. (See "Evaluation of patients with polyuria" and "Arginine vasopressin deficiency (central diabetes insipidus): Treatment".)

Permanent AVP-D is typically accompanied by impaired secretion of other anterior pituitary hormones, particularly thyroid-stimulating hormone (TSH) [22]. In a survey answered by 958 neurosurgeons, anterior pituitary insufficiency was cited as a complication of transsphenoidal hypophysectomy in 19 percent of cases [23].

Hyponatremia occurs in 8 to 24 percent of patients, presenting from postoperative day 1 to 10, with maximal antidiuresis at day 7 [20,24]. In one study of 52 patients without AVP-D, 7 percent had symptomatic hyponatremia (plasma sodium <125 mmol/L) with nausea, headache, and/or emesis [20].

Other — Other complications, apart from surgically related morbidity, include venous thrombosis and infection, which occurred in four and one patients, respectively, of 105 studied retrospectively [25]. Since the risk of thromboembolic complications is increased in Cushing syndrome, perioperative prophylaxis seems warranted in patients who are not ambulatory within a few days of surgery [26]. (See "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Thromboembolic events'.)

Is the patient cured?

Rates

Adults – There is no consensus on the criteria for "cure" after transsphenoidal surgery for Cushing disease. When judged in the immediate postoperative period, adult patients with persistent elevations in urine cortisol are not in remission. However, the remaining patients show a spectrum of biochemical features ranging from hypoadrenalism, with undetectable serum cortisol and plasma ACTH concentrations, to apparently normal ACTH and cortisol levels.

When judged by long-term outcome, patients with a postoperative serum cortisol less than 50 nmol/L (1.8 mcg/dL) have the highest long-term remission rates, 85 to 100 percent [27-29]. As noted, initial cure rates of up to 80 to 90 percent after transsphenoidal microadenectomy, based on postoperative serum cortisol concentrations <5 mcg/dL (138 nmol/L) within 14 days of surgery, have been reported [30-34]. In two studies, long-term remission rates were 65 and 80 percent in patients judged by this less stringent postoperative criterion [34,35].

Children – Similar surgical cure rates have been observed in children [36-38].

In one series of 42 children, remission occurred in 35 (83 percent), 26 of whom were carefully followed for a mean of 7.2 years. Seven subsequently relapsed after an average of 4.2 years [38]. Overall, pituitary surgery performed once or twice resulted in a long-term remission in approximately 80 percent of children.

In another series of 72 children, 70 achieved initial and 66 of 72 (92 percent) achieved long-term remission during follow-up of 24 to 120 months [39].

Macroadenomas – In general, patients with macroadenomas have lower cure rates.

As an example, of 137 patients with microadenomas operated on at a single center, 123 (90 percent) were cured initially. Of those, seven (6 percent) had a recurrence during a mean follow-up period of six years (range 1 to 11 years) [40]. Seventeen patients had macroadenomas, of whom 11 (65 percent) were cured initially; 3 of the 11 (27 percent) later had a recurrence.

In another study, initial remission was reported in five of eight patients with macroadenomas extending beyond the sella (63 percent) and in 43 of 52 with intrasellar macroadenomas (83 percent) [41]. Both of these studies defined surgical cure as a postoperative serum cortisol <5 mcg/dL (138 nmol/L).

In contrast, the cure rate (after surgery alone) in a series of 18 macroadenomas was only 12.5 percent when the more stringent criterion described above was used (serum cortisol <1.8 mcg/dL [50 nmol/L]) [42].

Late remission – Some patients appear to have a late remission, and early postoperative assessment of serum cortisol concentration is not sufficient to predict outcome, as illustrated by the following observations:

Some patients show a gradual decline in cortisol during the first three months after surgery, possibly indicating progressive necrosis of remaining tumor cells. This was illustrated in a study of 17 patients whose serum cortisol remained higher than 50 nmol/L (1.8 mcg/dL) within the first 14 days after surgery. However, serum cortisols had decreased to <50 nmol/L (1.8 mcg/dL) by three months after surgery, and all remained in remission during one to eight years of follow-up [43].

In a second study, 5.6 percent of 620 patients had late remission occurring at 38±50 days, suggesting that decisions about additional therapy should await additional testing in patients with persistent hypercortisolism after transsphenoidal surgery [44].

Biochemical criteria — A variety of criteria have been used to assess cure after transsphenoidal surgery [45]. The suggestions below apply only to those patients with active hypercortisolism at the time of surgery. The normal corticotropes in eucortisolemic patients on medical therapy (or those with symptom remission on glucocorticoid receptor blockers) or with mild or cyclic hypercortisolism may have recovered from previous inhibition, leading to normal cortisol levels after total tumor resection. In these patients, tests for the initial diagnosis of Cushing syndrome must be used to infer remission. (See "Establishing the diagnosis of Cushing syndrome".)

We currently suggest the following approach to assessing patient outcome in patients with active hypercortisolism:

Serum cortisol should be measured at 8 AM at least 24 hours after the last physiologic dose of glucocorticoid, beginning three to seven days after surgery, to assess cure [46]. Ideally, measurements are obtained for three consecutive days without glucocorticoid therapy.

The best criteria of cure are:

An undetectable serum cortisol concentration

An undetectable plasma ACTH concentration

Although an extremely low serum cortisol concentration (<1.8 mcg/dL, 50 nmol/L) is the best predictor of cure, some patients with low but detectable serum cortisol concentrations (2 to 4 mcg/dL [55 to 110 nmol/L]) that suppress with low-dose dexamethasone may remain in remission [46], as may those with cortisol values <5 mcg/dL (138 nmol/L) [34,35].

However, a persistently detectable serum cortisol concentration, even though it represents a major decrease from the preoperative concentration and is well within the normal range, may represent incomplete resection and an increased risk of recurrence. In these patients, measurement of cortisol every one to two weeks for up to three months may reveal a decline to less than 50 nmol/L (1.8 mcg/dL) [43]. Patients without a fully suppressed postoperative cortisol concentration may require some glucocorticoid replacement; ideally, this is 10 mg or less of hydrocortisone daily in the morning to avoid suppression of corticotropes. The blood sample is obtained before the morning hydrocortisone dose is taken. If the serum cortisol concentration becomes undetectable, the patient is considered cured.

Measurement of 24-hour urinary cortisol excretion may be useful since it confirms the serum cortisol concentration. The urine collection should begin at least 24 hours after the last small dose (10 mg or less) of hydrocortisone; a small maintenance dose (0.25 to 0.5 mg) of dexamethasone may be substituted before and during the collection. Excretion of less than <10 mcg/day (28 nmol/day) is consistent with cure.

Management of patients with intermediate postoperative values of serum or plasma cortisol should be individualized. If there is a reason to suspect that tumor tissue was left behind and that the normal values reflect tumor ACTH secretion, measurement of salivary cortisol at midnight can be helpful as it is likely to be abnormal with persistent disease. Lack of cortisol suppression to the overnight 1 mg dexamethasone suppression test may help confirm the suspicion of persistent disease. In these cases, additional therapy may be recommended. Patients with normal cortisol dynamics, in whom the normal corticotropes may not be suppressed, may be followed.

ACTH, CRH, or metyrapone stimulation tests are not helpful in these patients, because it is not clear how to interpret the results in this setting. A persistent response of cortisol and ACTH to the administration of intravenous desmopressin (10 mcg) may suggest a higher risk of recurrence [47-49]. (See "Desmopressin (DDAVP) stimulation test", section on 'Evaluating for remission of Cushing disease'.)

Factors that impact outcome

Neurosurgeon experience A neurosurgeon experienced with transsphenoidal surgery for Cushing patients can achieve an initial cure rate of 80 to 90 percent with microadenomas [30,31,36,40,50-53], but less than 60 percent with macroadenomas [40,54], although initial cure of 11 of 12 patients (92 percent) was reported from one center [55]. A meta-analysis of 18 reports since 1995 showed an overall initial cure rate for micro- and macroadenomas combined of 79 percent [56]. It is important to recognize that patients who are initially "cured" should be considered to be in remission rather than cured, as some will recur. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Corticotroph adenomas'.)

Less experienced neurosurgeons may have a cure rate as low as zero [32]. The cure rates with microadenomas depend upon pathologic confirmation of an adenoma or unequivocal demonstration of cure after resection, since approximately one-half of these tumors cannot be imaged in advance of surgery [57]. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Experience of the surgeon'.)

Surgical approach – It is likely that the approach to tumor resection influences the cure rate. In one study of 483 patients, 261 (54 percent) were considered intraoperatively to have an encapsulated adenoma confined to the anterior lobe of the pituitary gland; 166 (34 percent) had tumors invading the dura surrounding the pituitary; 11 (2 percent) had tumors within the posterior lobe; and in 45 (9 percent), no tumor could be identified at surgery. Remission occurred in 147 (89 percent) of the 166 patients with invasive tumors following resection that included the tumor and dural wall, all 11 patients with posterior lobe tumors following exploration of the posterior pituitary, and 34 (76 percent) of the 45 patients in whom no tumor could be found at surgery and a portion of the anterior lobe (30 to 100 percent) was removed. All 261 patients with an encapsulated adenoma had remission, following use of the histological tumor pseudocapsule so that the tumor is removed in a single specimen [15]. Increased use of the pseudocapsule approach may improve cure rates at other centers.

Location and features of the adenoma

All of the contents of the sella cannot be seen at surgery, so that some adenoma tissue may be missed. Diligent exploration of the entire gland is optimal if tumor is not recognized initially.

Diffuse corticotroph hyperplasia may be present. However, this is extremely rare.

The adenoma may arise in the pituitary stalk, which is not readily accessible to the surgeon. This occurred in 10 of 516 patients in one series, although all were successfully removed, with preservation of pituitary function in nine [58].

Adenomas that arise on the surface of the gland tend to be locally invasive; tumor cells in the interstices of the dura mater or in the cavernous sinus cannot be surgically excised [59].

Rarely, adenomas arising in ectopic sites may be the cause [60,61]. In one series of 626 patients with Cushing disease, five patients (0.8 percent) had parasellar tumors; a sixth patient appeared to have two distinct ACTH-secreting corticotroph adenomas, one in the periphery of the pituitary gland and the other in the cavernous sinus [62].

ACTH-secreting adenomas may rarely be located within the posterior lobe of the pituitary gland [63].

Recurrence — The true long-term cure rate is not known with certainty, in part because of differing criteria for cure and also because of inadequate follow-up [28,29,34,35,37,43,64-67].

The average reported interval to recurrence is approximately 40 months. However, this figure is in part an artifact of the relatively short duration of follow-up of many patients. One study prospectively analyzed the recurrence rate in 79 cured patients by survival analysis; 19 percent had recurrences by five years, and the cumulative recurrence rate was 26 percent at 10 years [67]. Others have reported a similar recurrence rate of 22 percent in 45 patients at a mean follow-up of nine years [68].

There is a similar time-to-recurrence in children; the average interval in seven children was 4.2 years (nine months to 6.2 years) [38].

The likelihood of recurrence can be predicted only in part by postoperative serum cortisol measurements. As an example, a recurrence rate as high as 12 percent was reported in patients with undetectable postoperative cortisol levels [29]. Complete normalization of adrenocortical function may be a better predictor of outcome. As an example, in one study of patients after transsphenoidal surgery, those who had low postsurgery serum cortisol concentrations and subsequent recovery of normal circadian rhythm and responsiveness to insulin-induced hypoglycemia had much lower recurrence rates (3.4 percent) than those who did not recover normal hypothalamic-pituitary-adrenal function (50 to 65 percent) [27].

Other hormone tests also provide prognostic information. In one report, for example, the recurrence rate increased from 11 percent in patients who had postoperative urinary cortisol values of 20 mcg/day (56 nmol/day) or less to 36 percent when the value was above 35 mcg/day (96 nmol/day; normal range 20 to 48 mcg/day [55 to 331 nmol/day]). Similarly, the recurrence rate increased from 8 percent in patients with a plasma ACTH concentration of 20 pg/mL (4.4 pmol/L) or less to 53 percent in those with a plasma ACTH concentration of 35 pg/mL (7.7 pmol/L) or more (normal range up 100 pg/mL [22 pmol/L]) [67].

Long-term monitoring — All patients should be reevaluated annually for several years and less frequently thereafter. This is particularly true in those who had initial intermittent hypersecretion of cortisol; these patients may seem to be cured after surgery but continue to secrete excess cortisol intermittently [69]. Reevaluation should include measurements of late-night salivary cortisol, a 24-hour urinary cortisol, and/or the 1 mg dexamethasone suppression test [65], using the same criteria as for diagnosis (see "Establishing the diagnosis of Cushing syndrome"). Patients should be encouraged to consider reevaluation at any time if they experience a return of their initial symptoms.

Treatment if surgery fails — For patients with clear, persistent disease after surgery (elevated urine cortisol excretion), one must first review the pathology results. If a tumor is not present on pathology, it is prudent to review the results of the tests for the differential diagnosis. In one study, 5 of 52 patients who failed surgery were found to have ectopic ACTH secretion [52]. In patients with equivocal results, additional testing may be needed.

Five therapeutic options remain in patients who are not cured in whom the diagnosis of Cushing disease appears to be correct:

Repeat resection of residual corticotroph adenoma, particularly if residual tumor is visible on MRI. Reoperation has a lower success rate than initial surgery. In three studies, 57 to 71 percent of patients who underwent early reoperation had evidence of biochemical cure [33,70,71]. However, many of them developed other pituitary hormone deficiencies as a result of the second procedure. In one study, immediate reoperation was most successful when the pathology indicated incomplete resection.

Irradiation of the pituitary gland. (See 'Pituitary irradiation' below.)

Medical therapy. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)

Adrenalectomy – Medical or surgical.

Medical adrenalectomy with mitotane, for example, may be used in conjunction with pituitary irradiation (algorithm 1). (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Mitotane'.)

Surgical adrenalectomy. (See "Persistent or recurrent Cushing disease: Surgical adrenalectomy", section on 'Surgical adrenalectomy'.)

The choice for therapy is individualized. For example, a young woman desiring fertility might choose to have adrenalectomy or repeat transsphenoidal exploration to avoid hypogonadism associated with radiotherapy and the teratogenicity of mitotane. A patient with extreme hypercortisolism might choose adrenalectomy to achieve rapid control.

PITUITARY IRRADIATION — Pituitary irradiation is the rational choice when pituitary surgery is either not the initial therapy or has failed. In addition, it may be considered as the initial therapy in children because it is as successful as transsphenoidal surgery [38,72,73].

The principal goal is to lower corticotropin (ACTH) secretion and thereby lower cortisol secretion to normal.

Type of radiation – Stereotactic radiosurgery (20 to 25 Gy) is considered the first choice if the adenoma is not close to the optic pathway; fractionated radiation (50.4 to 54 Gy) is used for those that are [74-79]. Stereotactic radiosurgery may be targeted when a pathologically confirmed lesion was partially resected; when the location of the tumor is not known, the entire sella must be radiated.

Efficacy – Reduction of cortisol to normal occurs in 50 to 80 percent of subjects. Addition of pharmacologic therapy increases the remission rates to 85 to 100 percent. Normalization of cortisol may occur somewhat faster after stereotactic radiosurgery than fractionated therapy, a median of 7.5 to 33 months versus 18 to 42 months [80]. Efficacy appears similar among all forms of stereotactic radiosurgery: Gamma Knife [74], linear accelerator [78], and proton [79].

Adrenal enzyme inhibitors – Patients with hypercortisolism should receive adrenal enzyme inhibitors (such as mitotane, metyrapone, or ketoconazole) to achieve eucortisolism until the radiation therapy is successful [1]. The ability of these agents to achieve eucortisolism should be evaluated prior to radiation therapy. If they are not effective, a different treatment should be considered. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)

Control of adenoma growth – A second goal of radiation therapy is control of adenoma growth, especially in corticotroph macroadenomas. All modalities of radiation therapy control adenoma growth in 90 to 100 percent of patients [74,76-78], similar to nonfunctioning adenomas.

Nelson syndrome – Corticotroph adenomas associated with Nelson syndrome may be less responsive to radiation than other corticotroph adenomas, but the data are limited [77].

Determine efficacy – To judge the effectiveness of radiation therapy, steroidogenesis inhibitor(s) can be stopped for a few days and 24-hour urine cortisol measured. Patients should receive teaching about adrenal insufficiency symptoms and should be instructed to return to the clinician if they experience such symptoms.

Fractionated radiation — A total of 42 to 45 Gy (4200 to 4500 rad) of conventional megavoltage radiation is delivered to the pituitary gland at a rate of 1.8 to 2 Gy/day (180 to 200 rad/day), usually via multiple collimated ports using a linear accelerator.

Primary therapy — The results of fractionated pituitary radiation as primary treatment can be summarized as follows:

Approximately 80 percent of children are cured [72].

The cure rate in adults is 15 to 53 percent [1,81].

Another 25 to 30 percent of adults are sufficiently improved that they require no additional therapy or only small doses of an adrenal enzyme inhibitor [1].

In contrast to the almost immediate reduction in ACTH and cortisol secretion after successful pituitary surgery, the maximal benefits of pituitary radiation do not occur for at least 9 to 12 months and occasionally as long as 18 to 24 months. Occasional "improved" patients may be cured several years after treatment. Children usually respond more rapidly, often within three months [72].

Secondary therapy — The percent of patients responding to fractionated radiation therapy may be somewhat higher after failed transsphenoidal surgery [75,82].

As an example, one study evaluated the efficacy of somewhat higher doses of radiation (48 to 54 Gy, mean 50 Gy) in 30 adults with persistent or recurrent Cushing disease after unsuccessful transsphenoidal surgery [75]. The remission rate increased progressively with time from 20 percent at six months to 43 percent at 12 months to 83 percent at 60 months. None of the 25 patients who were cured had a relapse of Cushing disease after remission was achieved.

In another study of 40 patients, 32 achieved remission at a follow-up interval of nine years [76].

Adverse effects — Serious side effects are rare in either adults or children with the treatment schedule described above given as primary therapy [1,83]. (See "Radiation therapy of pituitary adenomas", section on 'Risks/adverse effects'.)

Less than 5 percent of the patients developed clinical growth hormone or thyroid-stimulating hormone (TSH) deficiency, sometimes years after radiation.

With provocative testing, some degree of pituitary deficiency has been detected in a majority of patients who receive two to three times the currently recommended fractional dose [84].

Hypopituitarism was more frequent in the reports described above in patients with failed transsphenoidal surgery [75,76]. In these studies, 43 to 57 percent of the patients had growth hormone deficiency and approximately 33 percent had deficiencies of one or more other pituitary hormones. In one study of children, five of six who received both transsphenoidal surgery and radiation developed growth hormone deficiency, which was transient in two [85].

There is a longstanding controversy regarding a possible increased risk of death from cerebrovascular disease after radiation therapy:

A long-term, follow-up study of 342 patients with pituitary tumors (mostly nonsecreting tumors) treated by surgery and radiation suggested that radiation per se is not responsible for these deaths. The characteristics of radiation were not different in the cerebrovascular deaths (31 patients), compared with a control group that received radiation but did not have a cerebrovascular event [86]. Patients with Cushing disease (and acromegaly) were excluded from this study because of the increased incidence of cerebrovascular complications in these patients irrespective of the mode of therapy.

In a second study, 33 of 334 patients with pituitary adenoma died of cerebrovascular disease after radiation therapy, representing an increased relative risk of 4.11 compared with national age, sex, and interval mortality rates [87].

Higher cure rates can be attained by delivering up to 110 Gy (11,000 rad) of alpha-particle or proton beam external radiation over a few days [88,89] or 198Au or 90Y interstitial radiation [90,91]. These regimens, however, are associated with a higher incidence of side effects, especially hypopituitarism.

Stereotactic radiosurgery — Stereotactic radiosurgery with the 60Co Gamma Knife or the linear accelerator photon knife is another treatment option [92,93]. These instruments can deliver over 100 Gy (10,000 rad) of radiation with great precision in one treatment session (image 4A-B). (See "Stereotactic cranial radiosurgery".)

Results of primary therapy — In one series, 89 patients aged 5 to 67 with ACTH-producing tumors were treated with stereotactic radiosurgery, and 18 were followed for 12 to 22 years [94]. Of the 89 patients, 64 received one, and 25 had two or more courses of treatment. There were no treatment-related deaths, and vision and visual fields were not affected. Urinary cortisol levels gradually normalized in 83 percent, and no tumor recurrences were noted.

Results of secondary therapy — In a study of Gamma Knife after failed transsphenoidal surgery, 49 of 90 patients (54 percent) were cured, as indicated by normal urine cortisol excretion, on average approximately one year after treatment [74]. Ten patients (20 percent) had subsequent recurrence of hypercortisolism within five years.

Side effects of stereotactic radiotherapy — As with conventional fractionated radiotherapy, hypopituitarism is the most common side effect of radiosurgery.

In the series of 89 patients mentioned above, two-thirds developed radiation-induced endocrine deficiencies, some as late as 10 years after treatment [94].

In the series of 90 patients mentioned above, 20 (22 percent) developed new hormonal deficiencies. Five patients developed new visual deficits or third, fourth, or sixth cranial nerve deficits; two of these patients had undergone prior conventional fractionated radiation therapy, and four of them had received previous Gamma Knife therapy.

Other studies have shown that when side effects do arise with stereotactic radiation, they may occur within two years of treatment [95], although the median time is five years [96].

Stereotactic radiosurgery is more convenient for patients as it requires only one or two treatments, but it is generally more expensive than conventional radiation therapy (in the United States). There are not sufficient data to know if the side-effect profile differs between the two.

RESOLUTION OF CUSHING STIGMATA — In patients who are cured of Cushing disease or whose hypercortisolism is controlled, signs and symptoms of hypercortisolism improve rapidly and disappear over a period of 2 to 12 months. Thinning of the skin improves within weeks; muscle strength improves more slowly. Central obesity is usually lost, whereas patients with generalized obesity, especially if sustained for years rather than months, usually have difficulty losing the additional weight. Hypertension and glucose intolerance improve but may not be cured.

Unlike other forms of osteoporosis, the osteoporosis of Cushing syndrome improves rapidly during the first two years after cure and more gradually thereafter [97]. Unfortunately, vertebral compression fractures and aseptic necrosis of the proximal humerus and femur cause permanent deformity and are a major incentive for early cure of Cushing syndrome.

Five years after cure, 15 patients in one study had a higher prevalence of atherosclerosis and increased cardiovascular risk factors, probably due to residual abdominal obesity and insulin resistance [82]. Similar findings were reported in a study of 41 patients who had a higher prevalence of obesity and dyslipidemia than case controls at a mean follow-up duration of 11 years [98].

Resolution of neuropsychiatric symptoms after surgery is variable. (See "Epidemiology and clinical manifestations of Cushing syndrome", section on 'Neuropsychologic changes and cognition'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Cushing syndrome (The Basics)")

Beyond the Basics topics (see "Patient education: Cushing syndrome (Beyond the Basics)" and "Patient education: Cushing syndrome treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Cushing disease – Cushing disease is caused by pituitary corticotropin (ACTH)-secreting tumors. These tumors are almost always benign and are usually microadenomas (ie, <10 mm in diameter); in 30 to 40 percent, the microadenoma is so small that it is not detectable by magnetic resonance imaging (MRI), while in 10 to 15 percent, a macroadenoma is present. Treatment is aimed first at the anterior pituitary gland.

Transsphenoidal surgery – For most adult patients with Cushing disease, we suggest transsphenoidal surgery with an experienced surgeon as primary therapy (Grade 1B). (See 'Transsphenoidal surgery' above.)

The operative approach varies. Traditionally, the procedure involved transsphenoidal exploration through either a sublabial or endonasal approach, followed by use of a high-powered microscope that allowed for binocular vision. More recently, use of an endoscope, which does not provide binocular vision, has been advocated.

The extent of surgery varies. Ideally, the entire tumor is removed, while normal pituitary tissue is left behind. However, in adult patients in whom a microadenoma cannot be identified at the time of surgery and for whom fertility is not an issue, 80 to 90 percent of the pituitary should be resected, leaving a small island attached to the stalk.

The main surgical complication is arginine vasopressin deficiency (AVP-D), which occurs transiently in up to approximately 20 percent of patients but is rarely permanent. (See 'Arginine vasopressin deficiency' above.)

Biochemical assessment for cure – Serum cortisol should be measured at 8 AM at least 24 hours after the last physiologic dose of glucocorticoid, beginning two to seven days after surgery, to assess cure. Ideally, measurements are obtained for three consecutive days without glucocorticoid therapy. Although an extremely low serum cortisol concentration (<1.8 mcg/dL [50 nmol/L]) is the best predictor of cure, there are exceptions to this as described above. (See 'Biochemical criteria' above.)

Long-term monitoring – All patients should be reevaluated annually for several years and less frequently thereafter. This is particularly true for those who had intermittent hypersecretion of cortisol initially; these patients may seem to be cured after surgery but continue to secrete excess cortisol intermittently. (See 'Long-term monitoring' above.)

Management if surgery fails – The presence of tumor on pathology and the previous testing should be examined to ensure that the diagnosis is correct. If only a part of the tumor has been resected, immediate repeat surgery is an option. (See 'Treatment if surgery fails' above.)

For patients with a secure diagnosis in whom surgery has failed and with little or no radiologically detectable residual tumor, we suggest radiation therapy as the next step (Grade 2C). In patients with mild disease in whom the possibility of an additional two to four months of hypercortisolism is not deemed too risky, medical therapy with cabergoline or pasireotide is an alternative, recognizing that it is successful in only a minority of individuals. Radiation with adjunctive medical therapy may be best in those with dural invasion or who have unresectable remaining tumor. Adrenalectomy may be favored in those with severe hypercortisolism who need immediate cure or in women desiring pregnancy in whom steroidogenesis inhibitors are contraindicated.

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

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Topic 118 Version 17.0

References

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