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WORLD Journal of SURGERY @ 1996 by the Societe Internationale de Chirurgie
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Adrenalectomy for Treatment of Cushing Syndrome: Results in 122 Patients and Long-Term Follow-up Studies
Tsuneo Imai, M.D.,1 Hiroomi Funahashi, M.D.,1 Yuji Tanaka, M.D.,1 Junichi Tobinaga, M.D.,1
Masaki Wada, M.D.,1 Takako Morita-Matsuyama, M.D.,1 Yutaka Ohiso, M.D.,2 Hiroshi Takagi, M.D.1
1Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan
2First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan
Abstract. Patients with Cushing syndrome (n = 122) who underwent adrenalectomy from 1957 through 1993 were reviewed for survival and complications. Of the 122 patients, 70 had adrenocortical adenoma, 30 Cushing’s disease, 6 primary pigmented nodular adrenocortical disease (PPNAD), 7 other types of primary nodular hyperplasia, 5 adrenocortical carcinoma, and 4 ectopic ACTH syndrome. Sixty-five patients with adrenocortical adenoma are alive, and the survival rate was equal to the age-matched control population, when patients who died of the postop- erative complication were excluded. Of the patients with Cushing’s disease, 20 are alive; and 10 of 16 patients (63%) who were followed-up and evaluated had skin pigmentation. Four of sixteen patients (25%) developed Nelson’s syndrome. Four PPNAD patients and five with other types of nodular hyperplasia are alive. Most of these patients underwent bilateral total adrenalectomy, but some patients remitted after unilateral adrenalectomy. All of five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within 2 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 cure of signs and symptoms of glucocorticoid excess after total adrenalectomy is ensured, and prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing’s disease.
Cushing syndrome was first described 60 years ago [1]. This syndrome is the clinical manifestation of chronic glucocorticoid excess or hypercortisolism. Hypercortisolism occurs spontane- ously from five endogenous causes: adrenocortical hyperplasia secondary to excess secretion of adrenocorticotropin (ACTH) by a pituitary tumor; adrenocortical hyperplasia under the stimulus of ectopic ACTH or corticotropin-releasing hormone (CRH) secreted by nonpituitary tumors; adrenocortical adenomas that secrete cortisol autonomously; adrenocortical carcinomas that secrete cortisol autonomously; and primary adrenocortical nodu- lar hyperplasia.
Since synthetic glucocorticoids first became available for ther- apeutic use, adrenalectomy has provided a safe and reliable method of treating patients with Cushing syndrome [2]. Over the following two decades, the treatment of choice was adrenalectomy for Cushing syndrome of either pituitary origin or adrenal origin.
Thereafter transsphenoidal pituitary microdissection supplanted total adrenalectomy as the preferred treatment for Cushing’s disease [3]. Nevertheless, adrenalectomy remains one of the most important treatments for Cushing syndrome.
In this report we describe our experience with adrenalectomy for Cushing syndrome. The results of long-term follow-up and the current role of adrenalectomy for Cushing syndrome are dis- cussed.
Patients and Methods
From 1957 through 1993 a total of 122 patients underwent adrenal exploration with the diagnosis of Cushing syndrome at the De- partment 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 sub- groups: (1) adrenocortical adenoma; (2) Cushing’s disease; (3) primary pigmented nodular adrenocortical disease (PPNAD) [4]; (4) other types of ACTH-independent nodular hyperplasia; (5) adrenocortical carcinoma; and (6) ectopic ACTH syndrome. There were 23 males and 99 females. The mean age at operation was 32.6 years (range 1-63 years). The follow-up was 1 to 37 years (mean 14.1 years) for adrenocortical adenoma, 14 to 35 years (mean 24.6 years) for Cushing’s disease, and 2 to 25 years (mean 13.3 years) for primary nodular hyperplasia (PPNAD and other types of nodular hyperplasia). The pathologic distribution is shown in Table 1.
The patients were followed up to December 1994 by patient visits, correspondence, phone calls, physicians’ letters, 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). Of the 122 patients, two patients with Cushing’s disease could not be traced, but follow-up data on the other 120 patients were obtained. Survival for all patients after adrenalectomy was calculated using the method of Kaplan and Meier [5] and was compared with expected survival probabilities determined from age-matched normal subjects living in Japan. Comparisons of survival were made by the log-rank test.
| Pathologic diagnosis | Male (no.) | Female | Age (years) | Alive (no.) | Dead (no.) | Total (no.) |
|---|---|---|---|---|---|---|
| Adrenocortical adenoma | 6 | 64 | 35.5 | 65 | 5 | 70 |
| Cushing's disease | 9 | 21 | 25.7 | 20 | 8 | 30ª |
| Nodular hyperplasia | 3 | 10 | 30.9 | 9 | 4 | 13 |
| PPNAD | 1 | 5 | 16.6 | 4 | 2 | 6 |
| Others | 2 | 5 | 39.9 | 5 | 2 | 7 |
| Adrenocortical carcinoma | 3 | 2 | 40.0 | 0 | 5 | 5 |
| Ectopic ACTH syndrome | 2 | 2 | 31.3 | 0 | 4 | 4 |
| Total | 23 | 99 | 32.6 | 94 | 26 | 122ª |
PPNAD: primary pigmented nodular adrenocortical disease. “Two patients could not be found for followup.
Results
The survival of patients with Cushing syndrome is shown in Figure 1.
Adrenocortical Adenoma
Of 70 patients with adrenocortical adenomas, 65 are living. Four of five patients died within 3 months after adrenalectomy, the causes of death being pulmonary complication, coagulopathy, and adrenal insufficiency. One patient with adrenocortical adenoma died 9 years after adrenal surgery from cerebral hemorrhage. At autopsy the pituitary and remaining adrenal gland were normal. Survival in patients with adrenocortical adenomas paralleled the expected survival of the control population, when patients who died from postoperative complications were excluded. Cushing syndrome recurred in two patients owing to another contralateral adrenocortical adenoma 20 years after the first adrenalectomy. One of these patients underwent contralateral adrenalectomy and had pathologically proved adrenocortical adenoma; the syndrome remitted. The other patient has been undergoing medical therapy. Another two patients have been cared for in a mental health facility.
Cushing’s Disease
Four patients with Cushing’s disease died 7 months and 5, 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 (Fig. 1). Ten of sixteen (63%) patients who could be evaluated objectively had facial and finger pigmentation; four of them (25%) with severe pigmentation were diagnosed as having Nelson syndrome and underwent a pituitary operation [6]. All surviving patients have received oral glucocorticoid replace- ment therapy; and at the time of the survey, none of the patients had Cushing syndrome.
PPNAD
Two PPNAD patients died 1.5 and 13.0 years after total adrena- lectomy because of insufficient replacement of glucocorticoid and sudden death due to unknown factors, respectively. Another four patients are well under oral glucocorticoid replacement, and none
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has skin pigmentation or pituitary abnormality. The average age of these patients at the time of surgery was younger than that in the other groups (16.6 in this group versus 39.9 in other groups). One patient with PPNAD succeeded in delivering a child with glucocorticoid replacement 14 years after total adrenalectomy.
Other Primary Nodular Hyperplasia
Two patients of other types of nodular hyperplasia died 8 days and 11 years, respectively, after total adrenalectomy. Five patients are outpatients of our hospital, and they do not have skin pigmenta- tion. One patient also had aseptic necrosis of the head of the femur 2 years after total adrenalectomy. In one patient a large nodule in the left side showed strong cortisol production, but the right adrenal tissue had weak (but not absent) cortisol production, measured by in vitro steroidogenesis of dispersed adrenal tissues [7]. These results were in agreement with the laterality of uptake of 6b-iodomethyl-19-nor-cholest-5(10)-en-3b-ol-131I (iodomethyl norcholesterol). On the basis of this result, in the next patient we decided to remove only the right adrenal, which showed strong uptake of iodomethyl norcholesterol by scintigraphy. Figure 2 shows the macroscopic finding of the resected right adrenal gland in the second patient. There are multiple nodules, and the attached tissue between the nodules is not atrophic. The disease rapidly remitted after unilateral adrenalectomy, and the patient remained well for 2 years.
Adrenal Cancer and Ectopic ACTH Syndrome
The outcome for five patients with adrenocortical carcinoma and four patients with ectopic ACTH syndrome was poor. All patients with ectopic ACTH syndrome had a malignant neoplasm that secreted ACTH. In three patients the organ of origin was the pancreas, whereas in another it was the thymus. It was impossible to remove most of the original malignant tumor of ectopic ACTH syndrome and adrenocortical carcinoma. All nine patients died within 2 years.
Discussion
More than 70% of Cushing syndrome cases are classified as Cushing’s disease in Europe [8-10] and the United States [11], whereas in Japan 243 cases among 477 (50.9%) patients with Cushing syndrome were caused by adrenal adenoma in a survey conducted between 1982 to 1986 by the Japanese Ministry of Health and Welfare [12]. Of the other primary adrenocortical disorders, such as nodular hyperplasia and adrenal carcinoma, approximately 60% of the patients with Cushing syndrome in Japan underwent adrenal surgery as the primary treatment. The pathologic distribution of Cushing syndrome is different among nations, and adrenal surgery is the most widespread form of treatment for Cushing syndrome in Japan. Cushing’s disease accounted for 181 cases (37.9%) in this survey [12].
Untreated Cushing syndrome is associated with a 5-year mor- tality of 50% [13]. The prognosis of Cushing syndrome treated by adrenalectomy was different among the subgroups [14]. 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 receive glucocorticoid replacement, and the signs and symptoms of Cushing syndrome had disappeared. The quality of life in this group is excellent. One patient with adrenocortical adenoma died 3 months after unilateral adrenalectomy. Her postoperative glucocorticoid replacement was tapered off and discontinued 88 days after operation. Two weeks later, she was discovered dead in her bed. Severe diabetes and angina attacks were noted before and after operation. Relative adrenal insuffi- ciency might aggravate the general condition of such patients, so glucocorticoid replacement and careful observation are important for high risk patients with Cushing syndrome. It is important to pay careful attention not to lose a patient by operative complica- tion and to manage hypertension, diabetes mellitus, osteoporosis, mental disorders, and other complications of Cushing syndrome after adrenalectomy. Cushing syndrome recurred in two patients owing to another contralateral adrenocortical adenoma 20 years
after the first adrenalectomy. One patient underwent contralat- eral adrenalectomy and had pathologically proved adrenocortical adenoma; the syndrome remitted. Another patient has been receiving medical therapy. It is important to follow patients with Cushing syndrome due to adrenocortical adenoma for more than 20 years. These cases raise a question in the relation between multiple adrenocortical adenoma and nodular hyperplasia.
The prognosis for Cushing’s disease is favorable (Fig. 1). However, Nelson syndrome is a late complication of total adre- nalectomy for Cushing’s disease, and lifetime glucocorticoid re- placement is necessary. Of the 20 patients with Cushing’s disease who are alive, 16 could be assessed objectively regarding skin pigmentation. Pigmentation developed some time after adrena- lectomy in 10 of 16 patients (63%). Four patients (25%) had pituitary tumors (Nelson syndrome) and underwent a pituitary operation. The incidence of pigmentation and Nelson syndrome were reported to be 0% to 55% and 0% to 46%, respectively [15-19]. The incidence is higher in infants [20]. Among our patients, only 2 of 16 were under 20 years of age at the time of adrenalectomy, and now one has pigmentation and another underwent a pituitary operation for Nelson syndrome. Kemink et al. reported that the patient’s age is a simple predictive factor for the development of Nelson syndrome after total adrenalectomy for Cushing’s disease [21]. In our series, all four patients who developed Nelson syndrome were younger than 35 years at the time of adrenalectomy. Pigmentation and Nelson syndrome are major disadvantages of total adrenalectomy for Cushing’s disease. However, after successful removal of pituitary tumors, the pig- mentation disappeared rapidly. Insufficient glucocorticoid re- placement 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 physician in charge of primary care. Given the good results of the transsphenoidal operation [22-26], many patients with Cushing’s disease do not require adrenalectomy, although when indicated adrenalectomy is safe. The “cure” rate of transsphenoidal operation for Cushing’s disease has been re- ported to be 70% to 92%. A recurrence rate has been reported to vary up to 49%: the longer the period of follow-up, the higher the incidence of recurrence [26, 27]. Patients in whom the disease recurs and unimproved patients are candidates for bilateral total adrenalectomy [28]. Patients who undergo pituitary operation primarily or undergo pituitary irradiation are less likely to develop Nelson syndrome after total adrenalectomy [19]. The rapid cure of Cushing syndrome after total adrenalectomy is ensured, and the prognosis under careful glucocorticoid replacement is satis- factory. The long-term results of pituitary microoperation are still under study and should be compared with the results of adrena- lectomy for a large number of patients with Cushing’s disease in the future [10, 29].
The prognosis in cases of nodular hyperplasia was relatively poor (Fig. 1). The causes of late death are not elucidated precisely, but sudden death from unknown factors might be related to the complications of PPNAD [30]. The two patients of PPNAD who died 1.5 and 13.0 years after adrenalectomy were not studied precisely at the time of their death, but the macroscopic and microscopic findings were in agreement with PPNAD and immunohistochemical and in situ hybridization analysis of steroi- dogenic enzymes were previously reported [31]. Of 13 patients who showed nodular enlargement of adrenal glands and ACTH-
independent glucocorticoid excess, 6 were classified as having PPNAD based on the macroscopic and microscopic findings of the resected adrenals. The average age was younger than that of the other patients. The other seven patients were not commonly classified as having macronodular adrenocortical disease [32, 33] or ACTH-independent bilateral adrenocortical macronodular hy- perplasia (AIMAH) [34]. In one patient, it was difficult to determine whether the adrenal abnormality was nodular hyper- plasia or bilateral multiple adenoma. The nodules looked like adenoma, but the attached adrenal tissues were not markedly atrophied and the microscopic findings showed multiple small nodules in both adrenals. Basically, we employed bilateral total adrenalectomy for the treatment of primary adrenocortical nod- ular hyperplasia, and this patient underwent bilateral total adre- nalectomy. The in vitro steroidogenesis study revealed that most of the excess glucocorticoid was produced by the left adrenal. Preoperative iodomethyl norcholesterol scintigraphy did repre- sent the laterality of steroidogenic production of the adrenals. It is better to avoid lifelong glucocorticoid replacement with unilat- eral adrenalectomy, because there is a risk of adrenal insufficiency later in the patient’s life with total adrenalectomy [35]. Six patients died 7 months to 24 years after bilateral total adrenalectomy in our series, and the cause of death in three was adrenal insuffi- ciency. Considering this fact, we employed unilateral adrenalec- tomy in the next patient because iodomethyl norcholesterol scintigraphy showed strong uptake only in the right side and weak uptake in the left side. After the operation the patient showed rapid remission of the signs and symptoms of Cushing syndrome, and the glucocorticoid replacement was tapered off and discon- tinued within 6 months after adrenalectomy. The patient has been well and the left adrenal remained unchanged over the last 2 years. Although unilateral removal makes follow-up care more important, avoiding glucocorticoid replacement even for several years after the operation with no risk of adrenal insufficiency is a great advantage.
The prognosis was poor for patients with ectopic ACTH syndrome and adrenocortical carcinoma (Fig. 1). All of the patients with ectopic ACTH syndrome and adrenocortical carci- noma were in far-advanced stages when diagnosed. Despite various treatments, all patients died within 2 years.
Before 1970 diagnosis was made mainly by clinical manifesta- tions and biochemical and hormonal data. More recently, with the widely used and improving image diagnosis of adrenal glands, some cases were first noted as incidentalomas by CT or ultra- sonography and later diagnosed as Cushing syndrome. Before image diagnosis was developed, the general condition of the patient with Cushing syndrome was relatively poor compared with recent patients who are discovered relatively earlier. During the 1950s and 1960s the operative approach was a abdominal trans- peritoneal incision. After our experience with the abdominal incision, the posterolateral incision was chosen. For the trouble- some second-stage operation involving the posterolateral ap- proach, the posterior approach was tried briefly. The advantage of the posterior approach was the single-stage operation for bilateral adrenal resection without a need for position change during the operation. After 1981 the lateral approach was the preferred incision for either unilateral or bilateral adrenalectomy. It is necessary to change the position for a bilateral adrenalectomy using a lateral incision, with great care taken when positioning and moving the patient to avoid possible fractures. However, this
approach is superior to the others as reported earlier [36, 37]. Recently, laparoscopic adrenalectomy has become popular for treatment of adrenal neoplasms [38, 39]. This technique may take longer to perform than conventional open approaches, but it has the advantages of shortening the postoperative hospital stay and lessening postoperative analgesic requirements. This approach may decrease the risk of wound complications in patients suffering from hypercorticism. Laparoscopic adrenalectomy may be the preferred method for removing the adrenal lesions in patients with Cushing syndrome.
With the improvements of image diagnosis, anesthesia, periop- erative care, and the operative approach, adrenalectomy is a safe, reliable treatment for Cushing syndrome. In conclusion, adrena- lectomy continues to play an important role in the treatment of Cushing syndrome and is the treatment of choice for an adrenal adenoma, adrenocortical carcinoma, and primary adrenocortical hyperplasia. Furthermore, in selected cases bilateral total adrena- lectomy continues to be an alternative treatment for either Cushing’s disease or ectopic ACTH syndrome.
Résumé
Les dossiers de 122 patients ayant eu entre 1957 et 1993 une surrénalectomie pour syndrome de Cushing ont été analysés en vue d’étudier l’évolution et les complications. Parmi ces 122 patients, 70 avaient un adénome, 30 une maladie de Cushing, six avaient une maladie nodulaire pigmentée primitive (MNPP), cinq un cancer et quatre un syndrome de sécrétion ectopique d’ACTH. Soixante-cinq patients ayant un adénome surrénalien sont en vie; les chiffres de survie sont égaux à ceux de la population normale appariée pour l’âge, lorsqu’on exclue les patients décédés de complications postopératoires. Parmi les patients ayant une mala- die de Cushing, 20 sont en vie, et 10 des 16 (63%) patients réévalués ont une pigmentation cutanée. Quatre des 16 patients ont développé un syndrome de Nelson. Quatre patients atteints de MNPP et cinq patients ayant un autre type d’hyperplasie nodu- laire sont en vie. La plupart de ces patients ont eu une surréna- lectomie bilatérale, mais quelques patients ont été réadmis après surrénalectomie unilatérale. Tous les patients ayant un cancer (n = 5) et une sécrétion ectopique d’ACTH (n = 4) sont décédés moins de deux ans après l’opération. Le pronostic des patients ayant un adénome de la surrénale après surrénalectomie unilaté- rale est excellent, mais il est important d’éviter les complications peropératoires. La guérison rapide des signes et des symptômes secondaires à l’excès de glucocorticoïdes est assurée par la surrénalectomie totale. Le pronostic est satisfaisant sous opo- thérapie substitutive, si bien que la surrénalectomie totale est une alternative intéressante dans le traitement de la maladie de Cushing.
Resumen
Se revisaron los pacientes con síndrome de Cushing (122 en total) que fueron sometidos a adrenalectomía entre 1957 y finales de 1993. De los 122 pacientes, 70 tenían adenoma adrenocortical, 30 enfermedad de Cushing, seis enfermedad adrenocortical nodular pigmentaria primaria (EANPP), siete otros tipos de hiperplasia nodular primaria, cinco carcinoma adrenocortical y cuatro sín- drome de ACTH ectópica. Sesenta y cinco pacientes con ade- noma adrenocortical están vivos y la tasa de supervivencia fue
igual a la de la población normal, al excluir los pacientes que murieron por complicaciones postoperatorias. De los pacientes con enfermedad de Cushing, 20 están vivos y 10 de 16 pacientes (63%) que fueron seguidos y evaluados presentaron pigmentación de la piel. Cuatro de 16 pacientes (25%) desarrollaron síndrome de Nelson. Cuatro con EANPP y cinco con otros tipos de hiperplasia nodular están vivos. En la mayoría de los pacientes se practicó adrenalectomía bilateral total, pero algunos hicieron remisión luego de adrenalectomía unilateral. Todos los cinco con carcinoma adrenocortical y cuatro con síndrome de ACTH ec- tópica murieron dentro de los dos años siguientes a la operación. El pronóstico para pacientes con adenoma adrenocortical luego de adrenalectomía unilateral es excelente, aunque es importante evitar las complicaciones postoperatorias. Se puede asegurar la curación rápida de los signos y síntomas del exceso de glucocor- ticoides y un buen pronóstico luego de la adrenalectomía total bajo cuidadoso reemplazo de glucocorticoides, lo cual hace de la adrenalectomía total una alternativa en el tratamiento de la enfermedad de Cushing.
Acknowledgments
The authors are grateful to the physicians and surgeons of the endocrine groups of the Department of Surgery II and the First Department of Internal Medicine, Nagoya University School of Medicine, Japan, who referred patients and cooperated in their management, especially Professor A. Tomita (Aichi Medical University), and Drs. T. Yamaoka, K. Kako, and S. Mizuno. We also wish to thank Dr. Denis Baumgartner for helpful discussion.
References
1. Cushing, H .: The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull. Johns Hopkins Hosp. 50:137, 1932
2. Priestley, J.T., Sprague, R.G., Walters, W., Salassa, R.M .: Subtotal adrenalectomy for Cushing’s syndrome: a preliminary report of 29 cases. Ann. Surg. 134:464, 1951
3. Hardy, J .: Transsphenoidal microsurgery of the normal and patholog- ical pituitary. Clin. Neurosurg. 16:185, 1969
4. Grant, C.G., Carney, J.A., Carpenter, P.C., van Heerden, J.A .: Primary pigmented nodular adrenocortical disease: diagnosis and management. Surgery 100:1178, 1986
5. Kaplan, E.L., Meier, P .: Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457, 1958
6. Nelson, D.H., Meakin, J.W., Dealy, J.B., Matson, D.D., Emerson, K., Thorn, G.W .: ACTH-producing tumor of the pituitary gland. N. Engl. J. Med. 259:161, 1958
7. Lamberts, S.W.J., Bons, E.G., Bruining, H.A .: Different sensitivity to adrenocorticotropin of dispersed adrenocortical cells from patients with Cushing’s disease with macronodular and diffuse adrenal hyper- plasia. J. Clin. Endocrinol. Metab. 58:1106, 1984
8. Welbourn, R.B .: Some aspects of adrenal surgery. Br. J. Surg. 67:723, 1980
9. Kuhn, J.M., Proeschel, M.F., Seurin, D.J., Bertagn, X.Y., Luton, J.P., Girard, F.L .: Comparative assessment of ACTH and lipotropin plasma levels in the diagnosis and follow-up of patients with Cushing’s syndrome: a study of 210 cases. Am. J. Med. 86:678, 1989
10. Grabner, P., Hauer-Jensen, M., Jervell, J., Flatmark, A .: Long term results of treatment of Cushing’s disease by adrenalectomy. Eur. J. Surg. 157:461, 1991
11. Hamberger, B., Russell, C.F., van Heerden, J.A., et al .: Adrenal surgery: trends during the seventies. Am. J. Surg. 144:523, 1982
12. Demura, H., Takeda, R., Miyamori, I., et al .: Cushing’s syndrome in Japan with special reference to adrenocortical nodular dysplasia or hyperplasia. In: Controversies in Disorders of Adrenal Hormones, R.
Takeda, I. Miyamori, editors. Elsevier Science, Amsterdam, 1988, pp. 3-25
13. Plotz, C.M., Knowlton, A.I., Ragan, C .: The natural history of Cushing’s syndrome. Am. J. Med. 13:597, 1952
14. Watson, R.G.K., van Heerden, J.A., Northcutt, R.C., Grant, C.G., Ilstrup, D.M .: Results of adrenal surgery for Cushing’s syndrome: 10 years’ experience. World J. Surg. 10:531, 1986
15. Orth, D.N., Liddle, G.W .: Results of treatment in 108 patients with Cushing’s syndrome. N. Engl. J. Med. 285:243, 1971
16. Cohen, K.L., Noth, R.H., Pechinski, T.P .: Incidence of pituitary tumors following adrenalectomy: a long-term follow-up study of patients treated for Cushing’s disease. Arch. Intern. Med. 138:575, 1978
17. Manolas, K.J., Farmer, H.M., Wilson, H.K., et al .: The pituitary before and after adrenalectomy for Cushing’s syndrome. World J. Surg. 8:374, 1984
18. McCance, D.R., Russell, C.F.J., Kennedy, T.L., Hadden, D.R., Kennedy, L., Atkinson, A.B .: Bilateral adrenalectomy: low mortality and morbidity in Cushing’s disease. Clin. Endocrinol. (Oxf.) 39:315, 1993
19. Jenkins, P.J., Trainer, P.J., Plowman, P.N., et al .: The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing’s syndrome. J. Clin. Endo- crinol. Metab. 80:165, 1995
20. Thomas, C.G., Smith, A.T., Benson, M., Griffith, J .: Nelson’s syn- drome after Cushing’s disease in childhood: a continuing problem. Surgery 96:1067, 1984
21. Kemink, L., Pieters, G., Hermus, A., Smals, A., Kloppenborg, P .: Patient’s age is a simple predictive factor for the development of Nelson’s syndrome after total adrenalectomy for Cushing’s disease. J. Clin. Endocrinol. Metab. 79:887, 1994
22. Nakane, T., Kuwayama, A., Watanabe, M., et al .: Long term results of transsphenoidal adenomectomy in patients with Cushing’s disease. Neurosurgery 21:218, 1987
23. Mampalam, T.J., Tyrrell, J.B., Wilson, C.B .: Transsphenoidal micro- surgery for Cushing’s disease: a report of 216 cases. Ann. Intern. Med. 109:487, 1988
24. Guillaume, B., Bertagna, X., Thomsen, M., et al .: Transsphenoidal pituitary surgery for the treatment of Cushing’s disease: results in 64 patients and long term follow-up studies. J. Clin. Endocrinol. Metab. 66:1056, 1988
25. Tindall, G.T., Herring, C.J., Clark, R.V., Adams, D.A., Watts, N.B .: Cushing’s disease: results of transsphenoidal microsurgery with em- phasis on surgical failures. J. Neurosurg. 72:363, 1990
26. Tahir, A.H., Sheeler, L.R .: Recurrent Cushing’s disease after transs- phenoidal surgery. Arch. Intern. Med. 152:977, 1992
27. Favia, G., Boscaro, M., Lumachi, F., D’Amico, D.F .: Role of bilateral adrenalectomy in Cushing’s disease. World J. Surg. 18:462, 1994
28. Zeiger, M.A., Fraker, D.L., Pass, H.I., et al .: Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalec- tomy. Surgery 114:1138, 1993
29. Welbourn, R.B .: Survival and causes of death after adrenalectomy for Cushing’s disease. Surgery 97:16, 1985
30. Shenoy, B.V., Carpenter, P.C., Carney, J.A .: Bilateral primary pig- mented nodular adrenocortical disease: rare cause of the Cushing syndrome. Am. J. Surg. Pathol. 8:335, 1984
31. Sasano, H., Miyazaki, S., Sawai, T., et al .: Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases. Mod. Pathol. 5:23, 1992
32. Malchoff, C.D., Rosa, J., DeBold, C.R., et al .: Adrenocorticotropin- independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 68:855, 1989
33. Zeiger, M.A., Nieman, L.K., Cutler, G.B., et al .: Primary bilateral adrenocortical causes of Cushing’s syndrome. Surgery 110:1106, 1991
34. Aiba, M., Hirayama, A., Iri, H., et al .: Adrenocorticotropic hormone- independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing’s syndrome: enzyme histochemical and ultrastructural study of four cases with a review of the literature. Am. J. Clin. Pathol. 96:334, 1991
35. O’Riordain, D.S., Farley, D.R., Young, W.F., Jr., Grant, C.S., van
Heerden, J.A .: Long-term outcome of bilateral adrenalectomy in patients with Cushing’s syndrome. Surgery 116:1088, 1994
36. Russell, C.F., Hamberger, B., van Heerden, J.A., Edis, A.J., Ilstrup, D.M .: Adrenalectomy: anterior or posterior approach? Am. J. Surg. 144:322, 1982
37. Proye, C.A.G., Huart, J.Y., Cuvillier, X.D., Assez, N.M.L., Gam-
bardella, B., Carnaille, B.M.L .: Safety of the posterior approach in adrenal surgery: experience in 105 cases. Surgery 114:1126, 1993
38. Gagner, M., Lacroix, A., Prinz, R.A., et al .: Early experience with laparoscopic approach for adrenalectomy. Surgery 114:1120, 1993
39. Prinz, R.A .: A comparison of laparoscopic and open adrenalectomies. Arch. Surg. 130:489, 1995
Invited Commentary
J.A. Norton, M.D.
Department of Endocrine and Oncologic Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Cushing syndrome is a rare disease occurring in only 1 per million population [1]. The most common cause of hypercortisolism is iatrogenic-physicians prescribing prednisone. The most common cause of endogenous hypercortisolism is Cushing’s disease, which is an ACTH-producing pituitary tumor. Cushing’s disease ac- counts for approximately 80% of cases within the United States and Europe. Primary adrenal causes of hypercortisolism are next in incidence (15-18%) and include benign and malignant adrenal cortical tumors as well as micronodular and macronodular pri- mary adrenal cortical hyperplasia [2]. Finally, the least common cause of hypercortisolism is ectopic ACTH syndrome in which a tumor other than a pituitary tumor produces excessive ACTH. This disorder occurs in approximately 2% to 3% of instances [3, 4].
Untreated Cushing syndrome is a significant disease that has considerable mortality. In an early study the 5-year survival was 50% [5]. Patients die of hypertension, diabetes, stroke, myocardial infarction, pulmonary embolism, and unusual or severe infections. Therefore accurate recognition, diagnosis, and treatment of Cush- ing syndrome is mandatory. It is estimated that most physicians miss the diagnosis of hypercortisolism during their lifetime. However, as pointed out in the article by Imai et al., even with adequate treatment the natural history of patients with hypercor- tisolism can be problematic. Imai et al. provide the reader with important information about the long-term results of adrenalec- tomy for this disease. This commentary discusses their findings and suggests some insights to further improve outcome.
First, in patients with Cushing’s disease (pituitary adenoma) recent advances in management has nearly eliminated the role of bilateral adrenalectomy. As Imai et al. carefully document, bilat- eral adrenalectomy in these patients is associated with a high incidence of Addison’s disease and Nelson’s disease. One advance is the use of the corticotropin-releasing factor (CRH) stimulation test, which couples with the dexamethasone suppression test to establish the diagnosis in most patients [6, 7]. Another major breakthrough is petrosal sinus sampling for ACTH before and after CRH. Petrosal sinus sampling is able to make the diagnosis of Cushing’s disease unequivocally, and it provides important localization information so the surgeon knows which half of the pituitary contains the microadenoma [8]. Approximately 30% to 50% of pituitary adenomas in patients with Cushing’s disease do not appear on conventional imaging studies, including high reso- lution computed tomography (CT) and gadolinium enhanced
magnetic resonance imaging (MRI). Because of petrosal sinus sampling the surgeon can explore the side of the pituitary gland with the gradient; he either finds an adenoma or removes half the gland, which cures nearly every patient. One study reports a high success rate for more than 100 consecutive cases based on this strategy [9].
An interesting cause of Cushing syndrome is primary adrenal cortical hyperplasia. This disorder occurs in two forms: (1) primary pigmented micronodular hyperplasia (PPNAD), which commonly occurs in children and is associated with Carney’s syndrome [10, 11]; and (2) the newly described primary adrenal macronodular hyperplasia [12]. Both of these disorders are ACTH-independent and both require bilateral adrenalectomy with lifelong replacement therapy. Our studies agree with the results of Imai et al. that the labeled norcholesterol scan is useful for demonstrating the function of both adrenal glands and the need to excise both [13].
A major problem in the surgical management of patients with Cushing syndrome is postoperative Addison’s disease. In the article by Imai et al, hypoaldrenalism resulted in postoperative deaths of patients with adrenal adenoma, Cushing’s disease, and primary pigmented micronodular hyperplasia. Patients who have had bilateral adrenalectomy need both glucocorticoid (pred- nisone) and mineralocorticoid (Florinef Acetate) replacement for life. These patients need to wear a bracelet that notifies physicians and emergency personnel of their condition in the event of an acute illness or trauma. As noted in the study, patients whose adrenal adenoma is resected are cured of hypercortisolism and can expect a normal life expectancy. This fact makes the postop- erative death of one patient at 3 months after surgery tragic. Apparently, the glucocorticoids were discontinued, and the pa- tient died several weeks later of Addison’s disease. This case begs the questions: How long do you need to continue glucocorticoids after resection of an adrenal adenoma? When can you stop the medicine safely? A study designed to answer that question determined that it takes approximately 2 years before you can safely discontinue glucocorticoid replacement [14]. Glucocorti- coid replacement can be stopped when the patient has a normal cortisol response to ACTH stimulation [14].
In this study the authors noted the dismal prognosis of patients with either adrenal cortical carcinoma or ectopic ACTH syn- drome. Adrenal cancer is difficult to treat, but some patients (20%) survive long term [15, 16]. Aggressive surgery has been used to remove recurrent or localized metastatic tumor with some benefit [17-19]. Chemotherapy with mitotane at high doses with measurement of serum levels has been thought to be beneficial by some [20] but not others [16]. Nevertheless, the results with adrenal cancer may not be as dismal as suggested. Similarly, ectopic ACTH syndrome does not always have as poor a prognosis as the authors indicate. Survival with ectopic ACTH syndrome depends on the severity of the hypercortisolism and the malignant
nature of the tumor producing ACTH. The hypercortisolism associated with ectopic ACTH is severe. Despite drugs to ame- liorate the syndrome, often bilateral adrenalectomy is necessary to control it [4]. However, before performing adrenalectomy, the surgeon must consider the tumoral process and appropriate treatment. Tumors that cause ectopic ACTH, in decreasing frequency, include small cell lung cancer, bronchial carcinoid, thymic carcinoid, pancreatic islet cell tumor, medullary thyroid cancer, and pheochromocytoma. Obviously, bilateral adrenalec- tomy is seldom indicated in patients with small cell lung cancer, but it is indicated in patients with an unknown source of ACTH (these patients usually have an occult bronchial or thymic carci- noid) and patients with severe hypercortisolism who have a life expectancy of more than 6 months [4]. As suggested by Imai et al., islet cell tumors causing Cushing syndrome from ACTH have not been able to be cured of the tumor because they present with distant metastases [4, 21]. However, patients with ectopic ACTH from bronchial carcinoids are usually cured by lobectomy (85% five-year survival) despite the fact that 50% have lymph node metastases [4]. Finally, ACTH-producing pheochromocytoma is a rare cause of Cushing syndrome in which one adrenal has a tumor and the contralateral gland is hyperplastic. Resection of the pheochromocytoma is curative [22].
The authors performed most of the adrenalectomies through a flank approach. As they suggest, this procedure will soon be replaced by laporascopic adrenalectomy, which can already be done in the same amount of operative time with minimal blood loss and dramatically shortened convalescence [23, 24]. Small cortical adenomas and pheochromocytomas should be removed laparoscopically. Only large adrenal carcinomas and large pheo- chromocytomas should be done through an open anterior ap- proach.
In summary, adrenalectomy is often indicated for management of Cushing syndrome, but, treatment must also be focused on the cause of the syndrome. Following adrenalectomy the surgeon is responsible for adequate steroid replacement therapy. Remem- ber, the major cause of death following surgical treatment of Cushing syndrome is poorly controlled Addison’s disease. Every surgeon treating these patients must be alert to the appropriate method and duration of glucocorticoid and mineralocorticoid replacement.
References
1. Norton, J.A., Levin, B., Jensen, R.T. Cancer of the endocrine system. In: Cancer, Principles and Practice of Oncology, V.T. DeVita, S. Hellman, S.A. Rosenberg, editors. Lippincott, Philadelphia, 1993, pp. 1333-1435
2. Perry, R.R., Nieman, L.K., Cutler, G.B., et al .: Primary adrenal causes of Cushing’s syndrome: diagnosis and surgical management. Ann. Surg. 210:59, 1989
3. Orth, D.N .: Cushing’s syndrome. N. Engl. J. Med. 332:791, 1995
4. Zeiger, M.A., Pass, H.I., Doppman, J.D., et al .: Surgical strategy in the
management of non-small cell ectopic adrenocorticotropic hormone syndrome. Surgery 112:994, 1992
5. Plotz, C.M., Knowlton, A.L., Ragan, C .: Natural history of Cushing’s syndrome. Am. J. Med. 13:597, 1952
6. Chrousos, G.P., Shulte, H.M., Oldfield, E.H., et al .: The corticotropin- releasing factor stimulation test: an aid in the evaluation of patients with Cushing’s syndrome. N. Engl. J. Med. 310:622, 1984
7. Nieman, L.K., Chrousos, G.P., Oldfield, E.H., et al .: The ovine corticotropin-releasing hormone stimulation test and the dexamethe- sone suppression test in the differential diagnosis of Cushing’s syn- drome. Ann. Intern. Med. 105:862, 1986
8. Oldfield, E.H., Chrousos, G.P., Shulte, H.M .: Preoperative lateraliza- tion of ACTH-secreting pituitary microadenomas by bilateral and simultaneous inferior petrosal sinus sampling. N. Engl. J. Med. 312:100, 1985
9. Oldfield, E.H., Doppman, J.L., Nieman, L.K., et al .: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N. Engl. J. Med. 325:897, 1991
10. Travis, W.D., Tsokos, M., Doppman, J.L., et al .: Primary pigmented nodular adrenocortical disease. Am. J. Surg. Pathol. 13:921, 1989
11. Carney, J., Hruska, L.S., Beauchamp, G.D., Gordon, H .: Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin. Proc. 61:165, 1986
12. Zeiger, M.A., Nieman, L.K., Cutler, G.B., et al .: Primary bilateral adrenocortical causes of Cushing’s syndrome. Surgery 110:1106, 1991
13. Yu, K.C., Alexander, H.R., Ziessman, H.A., et al .: Role of preoper- ative iodocholesterol scintiscanning in patients undergoing adrenalec- tomy for Cushing’s syndrome. Surgery 118:981, 1995
14. Doherty, G.M., Nieman, L.K., Cutler, G.B., Jr., Chrousos, G.P., Norton, J.A .: Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing’s syndrome. Surgery 108:1085, 1990
15. Scott, H.W., Abumrad, N.N., Orth, D.N .: Tumors of the adrenal cortex and Cushing’s syndrome. Ann. Surg. 201:5866, 1985
16. Luton, J.P., Cerdas, S., Billaud, L., et al .: Clinical features of adreno- cortical carcinoma, prognostic factors and the effect of mitotane therapy. N. Engl. J. Med. 322:1195, 1990
17. Pommier, R., Brenna, M.F .: An 11 year experience with adrenocor- tical cancer. Surgery 112:1963, 1992
18. Potter, D.A., Strott, C.A., Javadpour, N., Roth, J.A .: Prolonged survival following six pulmonary resections for metastatic adrenal cortical carcinoma: a case report. J. Surg. Oncol. 25:273, 1984
19. Jensen, J.C., Pass, H.I., Sindelar, W.F., Norton, J.A .: Aggressive resection of recurrent or metastatic disease in select patients with adrenocortical carcinoma. Arch. Surg. 126:457, 1991
20. Van Slooten, H., Moolenaar, A.J., Van Seters, A.P., Smeek, D .: The treatment of adrenocortical carcinoma with o,p-DDD: prognostic implications of serum levels monitoring. Eur. J. Clin. Oncol. 20:47, 1984
21. Amikura, K., Alexander, H.R., Norton, J.A., et al .: Role of surgery in the management of adrenocorticotropic hormone-producing islet cell tumors of the pancreas. Surgery 118:1125, 1995
22. Chen, H., Doppman, J.L., Chrousos, G.P., Norton, J.A., Nieman, L.K., Udelsman, R .: Adrenocorticotropic hormone-secreting pheo- chromocytomas: the exception to the rule. Surgery 118:988, 1995
23. Gagner, M., LaCroix, A., Prinz, R.A., et al .: Early experience with laparoscopic approach for adrenalectomy. Surgery 114:1120, 1993
24. Gagner, M., LaCroix, A., Bolte, E .: Laparoscopic adrenalectomy in Cushing’s syndrome and pheochromocytoma [letter]. N. Engl. J. Med. 327:1033, 1992