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Original Article |
Departments of Endocrinology (P.A.K., A.B.G., G.M.B., P.J.J.) and Neurosurgery (G.S., F.A.), St. Bartholomew’s and The Royal London Hospitals, London EC 1A 7BE, United Kingdom
Address all correspondence and requests for reprints to: Dr. Paul J. Jenkins, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: p.j.jenkins{at}qmul.ac.uk.
Abstract
Total bilateral adrenalectomy remains the definitive procedure for cure in Cushing’s disease. It is complicated by the development of Nelson’s syndrome, the treatment of which remains troublesome. We report the long-term follow-up, median 17 yr (range, 8–22 yr), of 13 patients (3 males and 10 females) treated with pituitary surgery for Nelson’s syndrome at a median age of 35 yr (range, 21–67 yr). The presence of a pituitary mass lesion necessitated neurosurgery in all. Preoperatively, the median plasma ACTH level was 664 pmol/liter (range, 92–3665 pmol/liter); this fell to 29 pmol/liter (range, <2 to 1124 pmol/liter) postoperatively (P < 0.0005). Cutaneous hyperpigmentation was reduced in all and resolved in 11 patients. The pituitary tumor bulk was clearly reduced in 12 patients. There was no perioperative mortality. No patient developed a visual field defect attributable to surgery. New anterior pituitary hormone deficiency occurred in seven patients, and permanent diabetes insipidus occurred in five patients. At latest follow-up, the median plasma ACTH is 73 pmol/liter (range, <2 to 7759 pmol/liter); six patients have levels of less than 44 pmol/liter and also have a resolution of their pigmentation and no evidence of a recurrence of a pituitary mass lesion. We conclude that pituitary surgery is an efficacious treatment for mass lesions associated with Nelson’s syndrome, has long-term benefit with minimal side effects, and must be considered in the management of this distressing complication.
THE CURRENT TREATMENT of choice for pituitary-dependent Cushing’s syndrome (Cushing’s disease) is transsphenoidal resection of the corticotroph adenoma (1, 2). The cure rate following this procedure is variably reported as between 50% and 80% from major centers, depending upon the criteria used (3). For those patients with persistent ACTH-dependent disease, in whom radiotherapy with or without medical adrenocortical enzyme-blocking therapy is insufficient, total adrenalectomy offers the only definitive curative procedure to lower circulating cortisol levels adequately. Before the routine use of transsphenoidal hypophysectomy, this was used routinely for the initial treatment of Cushing’s disease (4). However, despite its efficacy, total adrenalectomy is complicated in up to 42% of patients by the development of Nelson’s syndrome (5), hyperpigmentation and elevated plasma ACTH levels, often with a locally aggressive pituitary tumor (6, 7). The incidence of this complication can probably be reduced by prophylactic pituitary irradiation (8), but progression may still occur. Although medical therapy or irradiation may reduce circulating ACTH levels (9, 10, 11) and hyperpigmentation (12), they may not be effective in alleviating the mass effects from expanding corticotroph pituitary tumors, which often require neurosurgical intervention. Previous reports detailing the use of neurosurgery for Nelson’s syndrome have tended to be of small series, with a variety of definitions as to what constitutes success and only short-term follow-up, all of which have rendered interpretation and comparison of results difficult. We report here the long-term follow-up of 13 patients at this institution who have required neurosurgery as part of their management for Nelson’s syndrome. Follow-up has ranged from 8–22 yr. Because of the known potential for aggressive local invasiveness of these tumors, total hypophysectomy was the surgical treatment attempted.
Patients and Methods
Patients (Table 1
)
The case records of more than 400 patients with Cushing’s syndrome who were followed up at this institution since 1946 were reviewed, in addition to those referred with partially treated Cushing’s disease or Nelson’s syndrome. Fifty-six patients had undergone adrenalectomy for pituitary-dependent disease (46 total, 6 subtotal, and 2 partial adrenalectomies, as well as 2 total adrenalectomies with reimplantation of adrenal tissue), of whom 24 had subsequently developed Nelson’s syndrome, defined as clinically evident hyperpigmentation and a plasma ACTH value greater than 44 pmol/liter (200 ng/liter) at 120 min after the usual morning dose of replacement hydrocortisone (8). All patients were taking glucocorticoid replacement with hydrocortisone in individually tailored doses. In common with the description by Nelson and his colleagues (13), the presence of an overt pituitary tumor was not considered necessary for the diagnosis, although it was often present.
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Eleven patients did not require neurosurgical intervention. Only one of this group had suprasellar disease that was felt at the time not to require neurosurgery, indeed shrinking under the influence of irradiation. This group had a lower median plasma ACTH level 120 min after the morning hydrocortisone of 124 pmol/liter (49–3740 pmol/liter) compared with 663 pmol/liter (92–3665 pmol/liter) in those requiring neurosurgery (P = 0.05).
As initial treatment for their Cushing’s disease, three patients received pituitary irradiation before adrenalectomy (patients 6, 7, and 10, with intervals of 6, 2, and 3 yr, respectively); one had transsphenoidal surgery (patient 12, 3 yr earlier), and one had received both surgery and adjunctive pituitary irradiation (patient 11, 3 yr earlier). Two patients had received prophylactic pituitary irradiation within 6 months of adrenalectomy (patients 5 and 13), and one patient had received pituitary irradiation as initial treatment for Nelson’s syndrome 3 months after the diagnosis (patient 1). The remaining six patients had pituitary irradiation subsequent to the neurosurgical intervention. At this institution, pituitary irradiation comprises 4500 cGy in 25 fractions given over 30 d via three fields from a 4- or 15-MeV linear accelerator.
Before neurosurgery, the median plasma ACTH level 120 min after the morning dose of oral hydrocortisone was 663 pmol/liter (range, 92–3665 pmol/liter), and all 13 patients had radiological evidence of a pituitary mass lesion (Table 1
). Since 1995, routine imaging of the pituitary fossa has used gadolinium-enhanced magnetic resonance imaging. However, all patients were initially investigated before the advent of magnetic resonance imaging. Previous imaging modalities have included computerized tomography (although many were also investigated before this modality became routine), plain skull x-rays, pneumoencephalography, and metrizamide cisternography. Before surgery, suprasellar extension was present in seven patients (54%), with invasion laterally into or beyond the cavernous sinus in five patients (38%), whereas in one patient (8%) the tumor was confined to the fossa. No patient had a detectable preoperative visual field defect using Goldmann perimetry or visual evoked responses. A cranial nerve III paresis was present in three patients (23%) preoperatively (complete in two, partial in one). Anterior pituitary hormone deficiencies were present in four patients (Table 2).
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The diagnosis of Cushing’s syndrome and Cushing’s disease was based on compatible clinical history and examination, serum electrolytes, circadian measurement of serum cortisol, and measurement of serum cortisol and plasma ACTH levels before and after both low- and high-dose dexamethasone suppression tests (0.5 mg and 2 mg, respectively, administered every 6 h for 48 h). Since 1980, the serum cortisol response to 100 µg iv CRH has additionally been used (14).
Function of the other anterior pituitary hormones was assessed at regular intervals. Basal assessment included serum total T4 and free T4, TSH, prolactin, LH, and FSH levels; also in men, testosterone and SHBG, and in women under 50 yr of age, estradiol and luteal phase progesterone levels. GH reserve was assessed on the responsiveness to insulin-induced hypoglycemia. Gonadotropin deficiency was diagnosed in men on the basis of a low serum testosterone level without elevation of LH/FSH; and it was diagnosed on the basis of amenorrhea and a low estrogen level without elevation of LH/FSH in women under 50 yr of age and by a lack of elevated LH/FSH levels in older women. Diabetes insipidus (DI) was diagnosed on the basis of polyuria in the presence of hypertonic serum and inappropriately low urine tonicity, and it was confirmed by water deprivation tests.
Serum cortisol was measured fluorometrically until 1982 and thereafter by a specific RIA. Plasma ACTH was measured by a specific extracted RIA using ACTH-(1–39) (inter- and intra-assay coefficients of variation of <10%; Ref. 15) reference standards from Bachem Chemicals (Torrance, CA). The minimum detectable concentration is 2.2 pmol/liter (10 ng/liter); normal range at 0900 h is less than 17.6 pmol/liter (<80 ng/liter). All of the remaining anterior pituitary hormone levels were measured by specific in-house RIAs and quality controlled by the United Kingdom External Quality Assessment Scheme.
Pituitary surgery
Nine patients underwent attempted total transsphenoidal hypophysectomy, whereas four had transcranial surgery-two through a sub-frontal approach and two through a pterional approach. In the transsphenoidal approach, the patient is routinely positioned in the supine, semi-sitting position, with the head fixed to a three-pin Mayfield clamp and usually rotated to the right. Position and trajectory are confirmed with image intensifier views before introducing the operating microscope. The procedure is routinely performed in our institution through a sublabial incision. The transsphenoidal approach was selected in nine cases in which adenomas were either entirely intrasellar, or a small suprasellar extension did not preclude its use. A pterional craniotomy and a bifrontal approach were used in two patients each. The operative side was selected on the basis of the lateral extension of the tumor. The tumor was found to be soft and friable in the majority of cases and was easily debulked using pituitary rongers and suction. When the capsule was densely adhered to the optic apparatus, the major vessels, or hypothalamus, no attempt at capsular removal was made, but patients were followed up with conventional radiotherapy if this had not already been given.
Statistics
Wilcoxon’s signed rank test was used to compare plasma ACTH levels pre- and postoperatively; the Mann Whitney U test was used to compare independent samples. All statistics were performed on Stats Direct version 1.9.5 (Stats Direct Ltd., Hertfordshire, UK).
Results
Postoperative plasma ACTH levels were reduced in all patients (Table 2). The median fall was 84% (range, 56%–99%), from a median level of 663 pmol/liter to 29 pmol/liter (range, <2 to 1124 pmol/liter; P < 0.0005, Fig. 1). Levels of less than 44 pmol/liter were achieved in 8 of 13 (62%) patients.
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Complications
There was no perioperative mortality. No patient developed a visual field defect or new cranial nerve palsy attributable to surgery; the patient with a partial cranial nerve palsy transiently worsened to a complete III nerve palsy, then followed by complete resolution. A temporary cerebrospinal fluid (CSF) leak occurred in two patients (both operated on via the transsphenoidal route), one of whom also developed meningitis-this was rapidly responsive to antibiotics and lumbar drainage. New anterior pituitary hormone deficiency occurred in seven of the nine patients with previously intact axes. Two of the four patients with a preoperative anterior hormone deficiency developed new deficiencies, becoming deficient of all anterior pituitary function-one operated on transcranially and the other transsphenoidally. Permanent DI occurred in five.
Long-term follow-up
At latest follow-up, median 17 yr (range, 8–22 yr), pigmentation remains resolved in eight patients (62%). Plasma ACTH levels are less than 44 pmol/liter in six patients (46%), whereas the levels in the remaining pair whose levels postoperatively were less than 44 pmol/liter, are at the latest assessment 73 pmol/liter and 198 pmol/liter. Among all patients, the median level is 73 pmol/liter (range, <2 to 7759 pmol/liter; Fig. 1). The fossa remains clear of tumor in nine patients (70%), with no regrowth of the residual tumor in two (15%). After surgery, further uncontrolled extensive tumor growth occurred in the remaining two patients, resulting in their death. One patient (patient 11) had an ACTH-secreting pituitary carcinoma that invaded anteriorly into both orbits, laterally into the cavernous sinuses, inferiorly into the sphenoid sinus, and posterior to destroy the clivus and further metastasized to the thoracic and lumbar spines and liver; death resulted from sepsis secondary to pneumonia. The second patient (patient 1) had a locally aggressive tumor, with superior invasion into the visual pathways causing gross visual field loss, lateral invasion through the cavernous sinus and beyond into the middle cranial fossa, resulting in a cavernous sinus syndrome and anterior invasion causing marked proptosis. Death resulted from coning when a massive bleed occurred in the tumor (Table 2).
Discussion
Transsphenoidal hypophysectomy is the only therapeutic modality that is able to fulfil all of the optimal aims for the treatment of Cushing’s disease as described by Orth and Liddle (4), namely, normalization of cortisol secretion, removal of any tumor threatening the health of the patient, avoidance of any permanent endocrine deficiency, and thus no dependency on medication. However, it does not always fulfill these aims, and it is reported to be curative in between 50% and 80% of patients depending on the criteria used (3). Cure is most likely with a microadenoma. Larger lesions may require irradiation, often with medical blockade. When this fails to control hypercortisolemia, total bilateral adrenalectomy is an effective and necessary procedure. However, a major disadvantage is the necessity for lifelong glucocorticoid and mineralocorticoid replacement therapy, with the risk of life-threatening hypoadrenal crises. The early reports of high perioperative morbidity and mortality (5, 16, 17) are now much less relevant, with modern anesthetic and surgical techniques. In addition, the potential development of Nelson’s syndrome remains a particular problem. The characteristics of those corticotroph adenomas that favor progression to Nelson’s syndrome are unknown because many of the patients described in this series had their primary treatment elsewhere, and adequate records were unavailable. We are unable to comment on this interesting issue.
Nelson et al. (6, 7) described 10 patients with increased pigmentation, expanding pituitary tumors, and markedly elevated plasma ACTH activity occurring, on average, 3 yr after bilateral adrenalectomy. Subsequent series have estimated its prevalence at between 0 and 42%, depending on the diagnostic criteria, the referral bias of the reporting center, and the length of follow-up (4, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27); previous data from our institution suggest a prevalence of 29% at a median of 1 yr from adrenalectomy (8). The present series does not permit us to assess the prevalence further due to the selected nature of the patients, some having already developed Nelson’s syndrome. In accordance with Nelson himself in a subsequent paper (13), the presence of an expanding pituitary mass is not essential for the diagnosis of this syndrome, only being present in 13 of 26 (50%) patients in the series, but merely increasing pigmentation and a lack of full suppressibility of plasma ACTH. Although prophylactic pituitary irradiation at the time of adrenalectomy may reduce or delay the subsequent occurrence of Nelson’s syndrome (8), the management of this complication once established may be difficult. Conventional irradiation may reduce circulating plasma ACTH levels and resolve pigmentation (12), but its effect on local mass effects is inconclusive. The growth of the pituitary mass is often controlled or it may shrink, but in some patients growth is progressive despite radiotherapy. The role of stereotactic radiosurgery has also yet to be clarified (28, 29, 30). Similarly, neuropharmacological therapy with sodium valproate (9) or dopamine agonists (11) is rarely effective. These tumors often develop markedly aggressive behavior, especially in the absence of radiotherapy, and this sometimes may be the cause of death.
Our data demonstrate that during prolonged follow-up of neurosurgical intervention in Nelson’s syndrome, almost 50% of patients have normal pigmentation, with a plasma ACTH level suppressing to less than 44 pmol/liter 120 min after the morning hydrocortisone dose, together with persistent absence of the pituitary tumor. Previous series on the efficacy of neurosurgery in the treatment of Nelson’s syndrome have reported success rates of between 10 and 70% (31, 32, 33, 34, 35, 36). However, there has been little consensus on the definition of success, which has been variably defined as a plasma ACTH level between 15 and 110 pmol/liter, basally, 2 or 24 h after the morning hydrocortisone or after 1 mg dexamethasone the previous evening, with or without the absence of demonstrable tumor. Long-term follow-up data have also often been lacking. Recently, Kemink et al. (37) published a series of 15 patients treated for Nelson’s syndrome, detailing continued clinical remission in 36% of patients after neurosurgery that had been followed up for a median of only 3 months. Kemink et al. also outlined the natural history of untreated Nelson’s syndrome in which six of eight patients, who were initially observed, required neurosurgery because of tumor expansion between 1.5 and 7 yr after diagnosis; one of this group died after pituitary apoplexy while awaiting elective neurosurgery. We have shown that neurosurgery offers a rapid and long-term reduction in plasma ACTH concentrations, which is associated with decreased pigmentation. Kemink et al. (37) have demonstrated a correlation between plasma ACTH levels 24 h after glucocorticoid replacement and the size of the pituitary mass lesion. However, plasma ACTH levels 24 h after the last dose of glucocorticoid replacement therapy bear little relation to the normal levels seen by the tissues (38). Plasma ACTH levels are, in our experience, usually above 176 pmol/liter 24 h after the last dose of replacement glucocorticoid in any patient with primary adrenocortical insufficiency, without a pituitary tumor, i.e. in Addison’s disease, and the use of this descriptor for the circulating ACTH level does not seem relevant (39).
The long-term effects of pituitary irradiation in reducing plasma ACTH in Nelson’s syndrome are well described (12), and Howlett et al. (12) detail the natural history of Nelson’s cases in which irradiation but not neurosurgery is required. All patients received pituitary irradiation, and many received adjunctive pituitary irradiation after neurosurgery; this will have influenced long-term ACTH levels. However, the immediate postoperative reduction of plasma ACTH levels in all patients that was sustained in the majority confirms the efficacy of neurosurgical intervention in this condition. More importantly, it offers a rapid and long-lasting resolution of the mass effects of local tumor growth with minimal morbidity. The two patients in whom there was subsequent aggressive local tumor expansion may reflect the phenotype of the original corticotroph adenoma. In our series, there was no visual field loss or permanent cranial nerve palsy attributable to surgery. Although the initial neurosurgical treatment of Cushing’s disease often allows a selective adenectomy to be performed, the frequent aggressive and locally invasive nature of tumors in Nelson’s syndrome usually dictates clearance of the fossa, with the consequent increased prevalence of panhypopituitarism. Despite this, the procedure is safe and well tolerated.
In conclusion, this series confirms the long-term efficacy, with minimal side effects, of neurosurgical intervention for mass effects of Nelson’s syndrome.
Acknowledgments
Footnotes
Abbreviations: CSF, Cerebrospinal fluid; DI, diabetes insipidus.
Received February 25, 2002.
Accepted September 7, 2002.
References
knife surgery of pituitary adenomas on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 61(Suppl 1):30–37
-knife radiosurgery in patient with Nelson’s syndrome. Clin Neurol Neurosurg 100:60–63[Medline]
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