Surgical management of Cushing’s syndrome
T. Imai*, T. Kikumori, H. Funahashi, A. Nakao
Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Summary - Patients with Cushing’s syndrome (137 total) who underwent adrenalectomy from 1957 through 1999 were reviewed for sur- vival and complications. Of the 137 patients, 83 had adrenocortical adenoma, 30 Cushing’s disease, seven primary pigmented nodular adrenocortical disease (PPNAD), eight adrenocorticotropin (ACTH)-independent macronodular hyperplasia, five adrenocortical carcinoma, and four ectopic ACTH syndromes. Seventy-eight patients with adrenocortical adenoma are alive, and their survival rate was equal to the age-matched control population, when patients who died of postoperative complications were excluded. Of the patients with Cushing’s dis- ease, 20 are alive, and ten of 16 patients (63%) who were followed and evaluated, had skin pigmentation. Four of 16 patients (25%) devel- oped Nelson’s syndrome. Five PPNAD patients and six with ACTH-independent macronodular hyperplasia are alive. All five adrenocorti- cal carcinoma patients and four with ectopic ACTH syndrome died within two years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid dis- appearance of signs and symptoms of glucocorticoid excess after total adrenalectomy is assured, and the prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing’s disease. @ 2000 Éditions scien- tifiques et médicales Elsevier SAS
adrenalectomy / Cushing’s syndrome / follow-up
Cushing’s syndrome is caused by hypersecretion of adrenocorticotropin (ACTH) (ACTH-dependent Cush- ing’s syndrome) or by primary adrenal hypersecretion of glucocorticoids (ACTH-independent Cushing’s syn- drome). Surgical management of Cushing’s syndrome by means of adrenalectomy is primarily indicated in ACTH- independent Cushing’s syndrome, and for some instances of ACTH-dependent Cushing’s syndrome. Since syn- thetic glucocorticoids became available for therapeutic use for the first time, adrenalectomy has provided a safe and reliable method of treating patients with Cushing’s syndrome [32]. In the two decades following its intro- duction, the treatment of choice was adrenalectomy for Cushing’s syndrome of either pituitary or adrenal origin. Thereafter, trans-sphenoidal micropituitary dissection supplanted total adrenalectomy as the preferred treatment for Cushing’s disease [15]. Adrenalectomy is now used principally for patients with primary adrenal disease, occult ectopic ACTH syndrome, or pituitary disease that is refractory to other treatments.
More than 70% of Cushing’s syndrome is classified as Cushing’s disease in Europe [11, 22, 46] and the USA
[14], whereas in Japan, 243 cases among 477 (50.9%) with Cushing’s syndrome were caused by adrenal ade- noma according to a survey conducted between 1982 to 1986 by the Japanese Ministry of Health and Welfare [7]. Among the other primary adrenocortical disorders such as nodular hyperplasia and adrenal carcinoma, approximately 60% of the patients with Cushing’s syn- drome in Japan were given adrenal surgery as the pri- mary treatment. The pathological distribution of Cush- ing’s syndrome is different among nations, and adrenal surgery is the most widespread form of treatment for Cushing’s syndrome in Japan.
This report will review our experience with adrenalectomy for Cushing’s syndrome. The results of long-term follow-up and the current role of adrenalec- tomy for Cushing’s syndrome are discussed.
PATIENTS AND METHODS
From 1957 through 1999, 137 patients underwent adrenal exploration with the diagnosis of Cushing’s syndrome at the Department of Surgery II, Nagoya University School of Medicine. On the basis of histologic and clinical findings related to the initial adrenal operation, patients were divided into the following subgroups: ACTH-dependent
* Correspondence and reprints.
| Pathological diagnosis | Male | Female | Total | Alive | Dead | Unknown |
|---|---|---|---|---|---|---|
| ACTH-dependent Cushing's syndrome | ||||||
| Cushing's disease | 9 | 21 | 30 | 20 | 8 | 2 |
| Ectopic ACTH syndrome | 2 | 2 | 4 | 0 | 4 | 0 |
| ACTH-independent Cushing's syndrome | ||||||
| Adrenocortical adenoma | 8 | 75 | 83 | 78 | 5 | 0 |
| PPNAD | 1 | 6 | 7 | 5 | 2 | 0 |
| ACTH-independent macronodular hyperplasia | 3 | 5 | 8 | 6 | 2 | 0 |
| Adrenocortical carcinoma | 3 | 2 | 5 | 0 | 5 | 0 |
| Total | 26 | 111 | 137 | 109 | 26 | 2 |
Cushing’s syndrome: a) Cushing’s disease, b) ectopic ACTH syndrome; ACTH-independent Cushing’s syn- drome: c) adrenocortical adenoma, d) primary pigmented nodular adrenocortical disease (PPNAD) [12], e) ACTH- independent macronodular hyperplasia [30], and f) adreno- cortical carcinoma (table I).
ACTH-dependent Cushing’s syndrome
Thirty patients underwent bilateral total adrenalectomy for Cushing’s disease before 1980 [5]. The follow-up was from 14 to 36 years (median = 25.8 years).
Four patients underwent bilateral total adrenalectomy for ectopic ACTH syndrome. However, the original ACTH- producing tumors were far advanced, and all patients died within one year.
ACTH-independent Cushing’s syndrome
Eighty-three patients underwent unilateral adrenalectomy for benign adrenocortical adenoma. The follow-up was from one to 38 years (median = 13.1 years).
Seven patients underwent adrenal resection for PPNAD [35]. The follow-up was from two to 29 years (median = 18.9 years).
Eight patients underwent adrenal resection for ACTH- independent macronodular hyperplasia [39]. The follow-up was from one to 21 years (median = 10.8 years).
Five patients underwent adrenal resection for adrenocor- tical cancer. However, the adrenal tumors were far advanced, and all patients died within two years.
The patients were followed up to December 1999 by patient visits, correspondence, phone calls, physicians’ let- ters, or autopsy reports. Information on some patients was obtained by family register or review of death certificates (permission number 6560, from the Ministry of Justice in Japan) in 1994 [16]. Of the 137 patients, two patients with Cushing’s disease could not be traced, but follow-up data on the other 135 patients were obtained.
Glucocorticoid replacement
From the day of the operation, the patients were treated with 100 mg hydrocortisone sodium succinate (Solu-Cortef, Pharmacia-Upjohn, Tokyo) administered intravenously at the time of ligation of adrenal vein and every eight hours after adrenalectomy. The dose was tapered to 100 mg and 50 mg every eight hours on postoperative days 2 and 3, respectively. Then the hydrocortisone tablets (Cortril, Pfizer, Tokyo) were administered orally, and the dose was tapered to 40 mg/day for one week. The patient’s clinical condition determines how much further to taper the dose to parallel clinical improvement. Most patients have been exposed to endogenous hypercortisolism for many years, and abrupt postoperative institution of replacement doses of glucocorticoids results in significant withdrawal symp- toms. Typically, patients are dismissed from the hospital on hydrocortisone 10 mg orally in the morning.
RESULTS
The survival of patients with Cushing’s syndrome is shown in figure 1 [20]. The results are grouped accord- ing to the final pathologic diagnosis.
ACTH-dependent Cushing’s syndrome
Cushing’s disease
Four patients with Cushing’s disease died seven months, five, 14, and 24 years after adrenal surgery because of acute adrenocortical insufficiency due to inadequate replacement of glucocorticoid, sudden death from unknown factors, acute bronchitis, and psy- chosis, respectively (figure 1). Ten of 16 (63%) patients who could be evaluated objectively had facial and fin- ger pigmentation, and four of them (25%) with severe pigmentation were diagnosed as having Nelson’s syn- drome and underwent a pituitary operation [28]. All surviving patients have received oral glucocorticoid
Survival
1.0
A
0.9
0.8
H
0.7
PN
0.6
MN
0.5
0.4
0.3
0.2
0.1
Ca+E
0.0
0
5
10
15
20
25
30
35
40
Years
replacement therapy, and at the time of survey, none of the patients had Cushing’s syndrome.
ACTH-independent Cushing’s syndrome
Adrenocortical adenoma
Seventy-eight of 83 patients with adrenocortical ade- nomas are alive. Four of five patients died within three months after adrenalectomy, the causes of death being pulmonary complication, coagulopathy, and adrenal insufficiency. One patient with adrenocortical adenoma died nine years after adrenal surgery from cerebral hem- orrhage. At autopsy, the pituitary and remaining adrenal gland were normal. Survival in patients with adreno- cortical adenomas paralleled the expected survival of the control population, when patients who died from postoperative complications were excluded. Cushing’s syndrome recurred in two patients due to another con- tra-lateral adrenocortical adenoma 20 years after the first adrenalectomy. One of these patients received contra-lateral partial adrenalectomy, had pathologi- cally proven adrenocortical adenoma, and the syn- drome remitted [18]. The other patient has been on medications.
PPNAD
Two PPNAD patients died 1.5 and 13 years after total adrenalectomy from insufficient replacement of gluco-
corticoid and sudden death due to unknown factors, respectively. Another five patients are well under oral glucocorticoid replacement and none of them has skin pigmentation or pituitary abnormality. The average age of these patients at the time of surgery was younger when compared with the other groups (18.2 in this group vs 34.3 in other groups). One patient with PPNAD succeeded in delivering a child with glucocor- ticoid replacement 14 years after total adrenalectomy.
ACTH-independent macronodular hyperplasia
Two patients of ACTH-independent macronodular hyperplasia died eight days and 11 years after total adrenalectomy because of incisional hernia and cere- bellar neoplasm, respectively. Six patients are outpa- tients of our hospital, and they do not have skin pig- mentation. One patient had aseptic necrosis of head of the femur two years after total adrenalectomy.
Operative approach
In the 1950s and 1960s, the operative approach was abdominal transperitoneal incision. After the scowl experience with abdominal incision, such as incisional hernia, incidental splenectomy, and postoperative hem- orrhage, postero-lateral incision was chosen. After 1981, the lateral approach was the preferred type of incision for either unilateral or bilateral adrenalectomy. Although it was necessary to change the position for a
bilateral adrenalectomy using a lateral incision, with great care in positioning and moving the patient to avoid possible fractures, this approach was superior to the others as reported earlier [33, 34]. Since 1996, lateral transabdominal laparoscopic adrenalectomy has been the treatment of choice for benign adrenal neoplasms in our institution [17]. Eleven patients with Cushing’s syndrome underwent laparoscopic adrenalectomy, nine of which were adrenocortical adenoma, one was PPNAD, and one was ACTH-independent macronodu- lar hyperplasia.
DISCUSSION
Without recognition and proper treatment, Cushing’s syndrome results in high rates of morbidity and mor- tality. Untreated patients have a five-year survival rate of 50%, with most deaths resulting from infection or cerebrovascular disease [31]. In the 1950s, the treat- ment of choice for Cushing’s syndrome was bilateral adrenalectomy, which markedly increased survival compared to untreated patients [45]. The prognosis of Cushing’s syndromes treated by adrenalectomy was very different between the subgroups [44]. As shown in figure 1, the prognosis for adrenocortical adenoma was excellent. Without early operative death, the cumulative survival rate is the same as in the age-matched group. At the time of the survey, all patients with unilateral adrenocortical adenoma no longer underwent gluco- corticoid replacement, and the signs and symptoms of Cushing’s syndrome had disappeared. The quality of life in this group is excellent. Patients with hypercorti- solism, whether the cause is endogenous or exogenous, have traditionally been regarded as at high risk when undergoing any surgical procedure. The principal risks have been those related to decreased wound-healing capabilities (decreased fibroblastic activity) and an increased risk of infection (decreased immunologic competence). One must be very careful not to lose a patient due to operative complications.
The prognosis for Cushing’s disease is favorable (figure 1). Nelson’s syndrome is a late complication of total adrenalectomy for Cushing’s disease and life- time glucocorticoid replacement is necessary. Out of the 20 patients with Cushing’s disease who are alive, 16 could be assessed objectively regarding skin pig- mentation. Pigmentation developed some time after adrenalectomy in ten out of 16 patients (63%). Four patients (25%) had pituitary tumors (Nelson’s syn- drome) and underwent a pituitary operation. The inci- dence of pigmentation and Nelson’s syndrome were reported to be 0 to 55%, and 0 to 46%, respectively [4,
19, 25, 26, 29]. The incidence is higher in infants [41]. In our patients, only two of 16 patients were under 20 years of age at the time of adrenalectomy, and now one has pigmentation and another underwent a pitu- itary operation for Nelson’s syndrome. Kemink et al. reported that the patient’s age is a simple predictive fac- tor for the development of Nelson’s syndrome after total adrenalectomy for Cushing’s disease [21]. In our series, all four patients who developed Nelson’s syndrome were younger than 35 years of age at the time of adrenalectomy. Pigmentation and Nelson’s syndrome are one of the major disadvantages of total adrenalec- tomy for Cushing’s disease. However, after the suc- cessful removal of pituitary tumors, the pigmentation disappeared rapidly. Insufficient glucocorticoid replacement was the cause of late death in three patients after bilateral total adrenalectomy. Education about glucocorticoid replacement is important for patients as well as for family members and for the primary-care physician.
Given the good results of the trans-sphenoidal oper- ation [13, 24, 27, 40, 42], many patients with Cushing’s disease will not require adrenalectomy. However, when indicated, adrenalectomy is safe. The ‘cure’ rate of trans-sphenoidal operation for Cushing’s disease has been reported to be 70-92%. A recurrence rate has been reported to vary up to 49%; the longer the period of fol- low-up, the higher the incidence of recurrence [8, 40]. Those patients in which the disease recurs or the unimproved patients are candidates for bilateral total adrenalectomy [48]. Bilateral adrenalectomy assumes a well-defined role in the treatment of Cushing’s dis- ease: 1) in cases in which pituitary treatment has been unsuccessful; or 2) pituitary surgery is a technical impossibility; and 3) in the presence of a rapidly wors- ening syndrome of hypercortisolism that cannot be ade- quately controlled with drug therapy because the latter is not tolerated by the patient and for which a clear-cut diagnosis cannot be made. Patients who undergo a pitu- itary operation primarily, or receive pituitary irradia- tion, are less likely to develop Nelson’s syndrome after total adrenalectomy [19]. The rapid cure of Cushing’s syndrome after total adrenalectomy is assured and the prognosis under careful glucocorticoid replacement is satisfactory [2, 3].
The prognosis in cases of nodular hyperplasia was relatively poor (figure 1). Of 15 patients who showed nodular enlargement of adrenal glands and ACTH- independent glucocorticoid excess, seven were classi- fied as having PPNAD based on the macroscopic and microscopic findings of the resected adrenals. The average age was younger than other patients. The
macroscopic and microscopic findings were in agree- ment with PPNAD, and immunohistochemical and in situ hybridization analyses of steroidogenic enzymes were previously reported [36]. The two patients with PPNAD who died 1.5 and 13 years after adrenalectomy were not studied closely at the time of death, but sud- den death from unknown factors might be related to the complications of PPNAD [37]. The other eight patients were not commonly classified as having macronodular adrenocortical disease [23, 47] or adrenocorticotropic hormone-independent bilateral adrenocortical macron- odular hyperplasia (AIMAH) [1].
The prognosis was very poor for patients with ectopic ACTH syndrome and adrenocortical carcinoma (figure 1). All of the patients with ectopic ACTH syn- drome and adrenocortical carcinoma were in the far advanced stages when diagnosed. Despite various treat- ments, all patients died within two years.
It is interesting to find the predominance of women in most of the categories: Cushing’s disease, 70%; adrenocortical adenoma, 90%; PPNAD, 86%; and ACTH-independent macronodular hyperplasia, 63%. These findings of female predominance are in agree- ment with the ones reported by van Heerden et al. [43].
A uniform elevation in factor VIII levels was demon- strated in 15 patients with Cushing’s syndrome, levels that normalized three to four months after operation [6]. Sjoberg et al. found postoperative thromboembolic occurrences in seven of 19 patients with Cushing’s syn- drome and demonstrated a positive correlation between the increase in factor VIII and the severity of the hyper- cortisolism [38]. Both reports suggested the prophylac- tic heparinization in patients undergoing operation for hypercortisolism. We have made routine use of intra- operative venous compression of the patients’ legs, and early and vigorous ambulation, instead of systemic heparinization.
Since October 1995, we have employed transabdom- inal lateral laparoscopic adrenalectomy for the treat- ment of Cushing’s syndrome [9]. Cushing’s syndrome is ideally suited for laparoscopic excision as most adrenal disorders are small and pathologically benign. The benefits of laparoscopic adrenalectomy include decreased operative blood loss, reduced analgesic requirements, shorter hospital stay and recovery time, and fewer late incisional complications [10, 17]. Laparoscopic adrenalectomy obtained aesthetically good results, as conventional adrenal surgery requires a relatively large incision because the adrenal glands are located deep in the retroperitoneal space. The relative risks in Cushing’s syndrome have been those related to decreased wound-healing capabilities and an increased
risk of infection. Laparoscopic procedure has the advantages in those risks, especially in obese and frag- ile patients with Cushing’s syndrome. The safety and efficacy of this procedure have been widely accepted.
With the improvements of image diagnosis, anesthe- sia, perioperative care, and the operative approach, adrenalectomy is a safe and reliable treatment for Cushing’s syndrome. In conclusion, adrenalectomy continues to play an important role in the treatment of Cushing’s syndrome and is the treatment of choice for an adrenal adenoma, adrenocortical carcinoma, and primary adrenocortical hyperplasia. Furthermore, in selected cases, bilateral total adrenalectomy continues to be an alternative treatment for either Cushing’s dis- ease or ectopic ACTH syndrome.
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