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Surgical Treatment of Adrenocortical Hyperplasia: 20-year Experience
Vol. 109, March
THE JOURNAL OF UROLOGY
Copyright © 1973 by The Williams & Wilkins Co.
Printed in U.S.A.
SURGICAL TREATMENT OF ADRENOCORTICAL HYPERPLASIA: 20-YEAR EXPERIENCE ALAN H. BENNETT, JOHN P. CAIN, ROBERT G. DLUHY, WILLIAM V. TYNES, J. HARTWELL HARRISON AND GEORGE W. THORN From the Departments of Surgery and Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts '
In 1912 and later in 1932 Cushing described a symptom complex in 13 patients with centripetal obesity, striae, diabetes mellitus, hypertension and psychiatric symptoms.' Although it was initially thought that all cases were caused by basophilic adenoma, it became evident that many were secondary to adrenal tumors, hypersecretion of pituitary adrenocorticotropin (ACTH) without pituitary tumor, ectopic production of ACTH and exogenous administration of glucocorticoids. and ACTH. Today, approximately 75 per cent of patients with endogenous Cushing's syndrome are suffering bilateral adrenal hyperplasia with hypothalamic-pituitary dysfunction. Therapy for classical bilateral adrenal hyperplasia has been directed at the pituitary and the adrenal glands. Although conventional pituitary radiation has not been satisfactory, more recent reports on the use of heavy particle radiation have been encouraging.2-• However, it is too early to assess the long-term results of heavy particle therapy. Surgical hypophysectomy produces good clinical remissions but may cause partial or total anterior and/or posterior pituitary insufficiency in addition to a significant operative mortality. Therefore, in most centers, therapy has been directed toward total or partial adrenalectomy. Analogous to subtotal thyroidectomy for the treatment of hyperthyroidism, subtotal adrenalectomy was performed in the early 1950's for treatment of bilateral hyperplasia.• Many patients later required re-exploration for recurrence of the disease. Thus, total bilateral adrenalectomy became the procedure of choice for Cushing's syndrome secondary to adrenocortical hyperplasia.
2 • 6 • 7 During the last 20 years 95 patients have. had surgical treatment for bilateral adrenal hyperplasia at the Peter Bent Brigham Hospital and they form the basis of this report. In this group of patients there are several who stand out as having unusual diagnostic and surgical problems which illustrate important pituitary-adrenocortical mterrelationshi ps.
CASE REPORTS
Case 1. A. K., a 16-year-old girl, was first seen with a long history of obesity, hirsutism, hypertension and primary amenorrhea. She underwent bilateral total adrenalectomy. Owing to a recurrence of symptoms and markedly elevated 17ketosteroids and 17-hydroxycorticoids, she underwent pituitary irradiation 4 years later. Thereafter, the patient once again became asymptomatic and steroid determinations returned to normal. However, 10 years later she noted the onset of increasing fatigability, weight gain and rounding of her face. Diagnostic study revealed a markedly elevated ACTH response with a loss of the normal diurnal variation of steroid levels. At laparotomy a mass was found in the right adnexa and frozen section revealed ectopic adrenocortical tissue. The right ovary and fallopian tube were removed with the mass of ectopic adrenal. The patient is now well 2 years following this surgical procedure without evidence of increased adrenocortical function. Case 2. C. R., a 31-year-old white woman, was first seen in 1954 with signs and symptoms of Cushing's syndrome. Chemical studies were consistent with bilateral adrenocortical hyperplasia and bilateral total adrenalectomy was done without complications. She did well for a 3-year period when increased pigmentation and visual field impairment with an enlarged sella turcica and high levels of plasma ACTH developed. 8 A 20
Accepted for publication June 6, 1972. Cushing, H.: 'l'he basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull. Johns Hopkins Hosp., 50: 137, 1932. 2 Orth, D. N. and Liddle, G. W.: Results of treatment in 108 patients with Cushing's syndrome. New Engl. J. Med., 285: 243, 1971. 3 Sosman, M. C.: Cushing's disease-pituitary basophilism. Amer. J. Roentgen., 62: 1, 1949. • Linfoot, J. A., Lawrence, J. H., Born, J. L. and Tobias, C. A.: The alpha particle or proton beam in the radiosurgery of the pituitary gland for Cushing's disease. New Engl. J. Med., 269: 597, 1963. 'Priestley, J. T., Sprague, R. G., Walters, W. and Salassa, R.: Subtotal adrenalectomy for Cushing's syndrome; preliminary report of 29 cases. Ann. Surg., 134: 464, 1951. 1
'Konnak, J. W. and Cerny, J. C.: The surgical treatment of Cushing's syndrome. J. Urol., 102: 653, 1969. 7 Egdahl, R. H. and Melby, J. C.: Recurrent Cushing's disease and intermittent functional adrenal cortical insufficiency following subtotal adrenalectomy. Ann. Surg., 166: 586, 1967. • Nelson, D. H., Meakin, J. W. and Thorn, G. W.: ACTH-producing pituitary tumors following adrenalectomy for Cushing's syndrome. Ann. Intern. Med., 52: 560, 1960. 321
322
BENNETT AND ASSOCIATES
gm. chromophobe adenoma of the pituitary was removed. Comment: Ten cases of pituitary adenoma have been found in this series, manifesting themselves from 1 to 13 years following surgical removal of the adrenal glands. Case 3. M. C., a 47-year-old female lawyer, was initially seen in 1947 with classical Cushing's syndrome. She underwent pituitary irradiation and had marked improvement for approximately 1 year when many signs and symptoms of Cushing's syndrome recurred. She underwent left adrenalectomy; the gland appeared somewhat small but showed some evidence of hyperplasia on pathological examination. Two weeks later, because of no change in the clinical picture or the steroid levels, the right side was explored and a 3.0 cm. adenoma was discovered, the obvious cause for Cushing's syndrome. Comment: In a recent review of experiences with adrenal tumors, 15 cases of adenoma causing Cushing's syndrome were found. 9 In 4 patients the differential between adrenocortical hyperplasia or adenoma was not made until surgical exploration. Case 4. B. P. is a typical example of a recurrence of Cushing's syndrome following subtotal adrenalectomy. She had hypertension, weight gain, striae and several other symptoms of Cushing's syndrome in 1953 at the age of 44 years. She underwent bilateral subtotal adrenalectomy in 1954 and did well for 13 years when hypertension recurred as well as other signs and symptoms of Cushing's syndrome. Chemical studies revealed increased 17-hydroxycorticoid and 17-ketosteroid excretion. Bilateral remnant adrenalectomy revealed 4 gm. tissue on the left side and 3.6 gm. on the right side. Pathologic examination revealed cortical hyperplasia. During the 4 years following the last procedure the woman has been asymptomatic. Comment: Seven patients in the entire group had remnant adrenalectomy for recurrent symptoms. CLINICAL FEATURES OF HYPERADRENOCORTICISM OWING TO HYPERPLASIA
Of the 95 patients who had adrenal operations for treatment of Cushing's syndrome secondary to bilateral adrenal hyperplasia, the mean age was 32.2 years with a 2 to 1 ratio of female to male subjects. The diagnosis of excessive glucocorticoid secretion was made on clinical (table 1) and biochemical grounds. In 76 per cent of the patients classical symptoms of Cushing's syndrome, including centripetal obesity, hirsutism, hypertension, carbohydrate intolerance, striae, plethora and psychiatric disturbances, were present. Three 9 Bennett, A. H., Harrison, J. H. and Thorn, G. W.: Neoplasms of the adrenal gland. J. Urol., 106: 607, 1971.
patients were suffering ectopic ACTH production and had marked signs and symptoms of excessive cortisol secretion. The biochemical diagnosis was made on the basis of increased urinary 17 -hydroxycorticoid and 17-ketosteroid determinations and failure of suppression of urinary 17-hydrocorticoid excretion to less than 3 mg. per day with 2 mg. dexamethasone per day. In some patients there was only minimal elevation of 17-hydroxycorticoid secretion but in these cases there was reversal of the normal diurnal steroid excretion pattern. Differentiation between adrenal neoplasia and hyperplasia was usually possible on the basis of high dosage dexamethasone suppression (2 mg. by mouth every 6 hours for 48 hours). In Cushing's syndrome associated with either adrenal neoplasia or bilateral hyperplasia caused by ectopic ACTH production, high dose dexamethasone did not significantly suppress urinary 17-hydroxycorticoid excretion. The use of excretory urography (IVP) had little to offer in the differentiation of hyperplasia from neoplasia (table 2). However, arteriography was useful in the localization of adrenal adenoma once the diagnosis was suspected clinically and confirmed by laboratory investigation. 4 Although adrenal venography is useful in the localization of mineralocorticoid-producing aderiomas, its use in localization of glucocorticoid adenomas was hazardous since the glands and adrenal veins tend to be extremely friable. TREATMENT
During the first 10 years a combination of treatments was used (table 3). Seven patients who had had subtotal adrenalectomy on each side were referred from other hospitals. Seven of the 13 patients who had subtotal adrenalectomies required removal of adrenal gland remnants for recurrence of their disease from 2 to 14 years following initial treatment. However, 70 of the 95 TABLE
1. Presenting features (95 pts.)
Classical Cushing's syndrome Hypertension Diabetes Osteoporosis Renal calculi Significant psychiatric problems
76 74 57 23 8
13
Ectopic ACTH syndrome: Ca oflung Ca of liver Malignant thymoma
TABLE
2. Radiological studies (95 pts.) Studies Pos./No. Pts. Studied
IVP with or without tomography abnormal
9/76
Angiography
4/6
Adrenal venography Retroperitoneal air study
1/1 1/1
323
SURGICAL TREATMENT OF ADRENOCORTICAL HYPERPLASIA
patients underwent bilateral total adrenalectomy as their primary treatment. Nine of these patients had staged adrenalectomies, all in the early 1950's; the time lapse between procedures ranged from 2 weeks to 2 years with an average of 4 months. The approach to the adrenal gland can be from the flank position, resecting the 11th or 12th rib, or with the patient prone again with resection of the 11th or 12th rib, through a transabdominal or transthoracic incision. In patients with Cushing's syndrome who have moderate to severe truncal obesity we have found the flank incision to be most beneficial as far as easy access to the adrenal gland is concerned (table 4). The panniculus of these patients when they are prone makes for a difficult approach in the posterior position. When they are turned on their side and the standard flank incision is used, the fat will fall forward and not interfere with exposure. The best possible exposure is gained through resection of the 11th rib. Particular attention must be paid to hemostasis since these patients are on high doses of steroids during the operation and in the postoperative period and are quite prone to infection and wound problems. With good exposure blood loss can be kept at a minimum. In this series the average blood replacement was 0.8 units per case with a range of O to 7 units; the 7 unit replacement occurred after injury to the inferior vena cava in 1 case. After the retroperitoneal space is entered, Gerota's fascia is incised and the upper pole of the kidney is mobilized and carefully displaced caudally, giving excellent exposure of the adrenal gland. Dissection of the gland is begun along the inferior and lateral borders. Either ties of 3 and 2-zero silk or Cushing (week) clips are used to secure blood vessels. On the right side the adrenal vein is quite short and care must be taken to secure this vessel. It is usually the last attachment before removing the gland on the right side. On the left side the gland has the propensity to extend down to the renal pedicle and care must be taken to avoid injury to the renal artery or vein. After the adrenal glands are reT ABLE
moved no drains are necessary and the wounds are closed in the standard fashion. OPERATIVE AND POSTOPERATIVE STEROID MANAGEMENT
On the day prior to operation a supplemental dose of 50 mg. cortisone acetate was commonly given intramuscularly at 7 p.m. On the day of the operation 100 mg. cortisone acetate was given intramuscularly 1 hour before the patient was taken to the operating room. During the operative procedure a continuous infusion of glucocorticoid (100 mg. hydrocortisone sodium succinate in 1,000 cc 5 per cent dextrose and saline) was administered at a rate of 10 to 15 mg. per hour. Postoperatively, 50 to 100 mg. hydrocortisone sodium succinate was distributed in the remaining intravenous solutions and 50 mg. cortisone acetate was given intramuscularly at 7 p.m. The total cortisone dose on the day of the operation was usually 300 mg. (table 5). During the next 7 days the intramuscular and intravenous cortisone was gradually tapered in 30 per cent decrements to maintenance levels (usually 37.5 mg. per day). Tapering was interrupted and cortisone dosage was increased if an important complication such as sepsis occurred. Oral steroid medications were resumed when fluids were allowed by mouth (usually 4 or 5 days postoperatively). Antacids or milk was given with all oral steroid doses. Mineralocorticoid therapy was usually begun when the total cortisone dose was less than 100 mg. Daily mineralocorticoid therapy was either desoxycorticosterone acetate (5 mg. 1 or 2 times daily) intramuscularly or 9-alpha fluorohydrocortisone (0.1 mg. 1 or 2 times daily) by mouth. Daily serum electrolytes, creatinine and body weights (if possible) were used to design the patient's dietary sodium requirements and dosage of salt-retaining hormone. PATHOLOGY
Table 6 shows the results of the pathological examination of these glands. Hyperplasia of the zona fasciculata was noted in more than 75 per
3. Treatment (95 pts.) TABLE
No. Pts. Pituitary irradiation before operation
29
Bilateral adrenalectomy (I stage) Bilateral adrenalectomy (staged)
61 9 3
Unilateral adrenalectomy and pituitary irradiation Unilateral adrenalectomy
Subtotal adrenalectomy
13
Removal of adrenal gland remnants Removal of ectopic adrenal tissue ( ovary)
TABLE
4. Approach to adrenal gland (95 pts.) Glands Removed
Flank (11th or 12th ribs) Posterior (11th or 12th ribs) Transabdominal
5. Steroid replacement in patients undergoing bilateral adrenalectomy
159 21
Day of operation Postop. day:
I 2 3 4 5 6 7
8 9 IO
* Reduced to I time daily.
Cortisone Acetate
9-Alpha Fluoro-
(mg.)
(mg. 2 times daily)
hydrocortisone
300
300 200 200 150 150 100 100 75 75 50
0.1 0.1 0.1 0.1 0.1 0.1 0.1 *
324
BENNET!' AND ASSOCIATES
cent of the cases. The average adrenal gland weighed 11.1 gm. with a range of 5.2 to 30 gm. The average weight of a normal adrenal gland is 3.5 to 5 gm., so that even when the pathological examination was normal, the gland weight was elevated in these patients.
TABLE
8. Causes of death (95 pts.)
Cardiovascular Electrolyte disturbance
Intra-abdominal hemorrhage Gastrointestinal hemorrhage Pneumonia, septic shock Pulmonary embolus Suicide
Unknown
COMPLICATIONS AND RESULTS
Major intraoperative complications were infrequent in this group of patients (table 7). Most troublesome were wound infections but the majority were superficial in nature and did not prolong hospitalization. Also during the period of postoperative high steroid administration, acute anxiety and manic reactions were frequently encountered. Five deaths occurred in the immediate postoperative period: 1 associated with severe hypokalemia in a patient with malignant thymoma, 1 with recurrent pulmonary emboli (9 days postoperatively), 1 with intra-abdominal bleeding from the operative site (1 day postoperatively), 1 of massive gastrointestinal bleeding (7 days postoperatively) and 1 septic shock complicating pneumonia (table 8). Four others died during the following year (2 of unknown causes, 1 of myocardial infarction and 1 by suicide). One died of a myocardial infarction at a later date and 12 were lost to followup. Seventy-three patients were well 2 to 20 years postoperatively although 12 were being treated for hypertension (table 9). Seven patients had experienced 1 or more addisonian crises associated with hypotension, hyponatremia and hyperkalemia that required hospitalization. Because of the occurrence of postoperative addisonian crises, a teaching program was instituted for adrenalectomized patients. Prior to discharge from the hospital patients are instructed in the fundamentals of steroid replacement therapy.
10
TABLE
9. Postoperative status (95 pts.)
Clinically well, 2 to 20 years postop. Well with hypertension Dead Lost to followup
61 12 10 12 95
Patients are instructed to automatically increase their glucocorticoid intake for stressful situations, such as febrile illness, dental extraction and so forth. Patients are also taught to administer steroid parenterally if they are vomiting or otherwise unable to take medications by mouth. Patients are discharged with a kit (containing needles, syringes and a parenteral steroid preparation) and are urged to purchase and wear a medialert bracelet, identifying them as adrenalectomized individuals. A more troublesome complication was the development of hyperpigmentation associated with sella turcica enlargement and pituitary tumor. This occurred 2 to 10 years after the initial bilateral adrenalectomy and was successfully treated with amelioration of pigmentation by surgical hypophysectomy (4 cases) and pituitary irradiation (6 cases). SUMMARY
TABLE
6. Pathology (95 pts.)
Hyperplasia zona fasciculata Normal No report (operation done elsewhere) Congested, hemorrhagic
TABLE
71 13 7
4
7. Complications of operation (95 pts.)
Wound infection (severe) Wound infection (superficial) Cerebrovascular accident Myocardial infarction Pneumonia Urinary tract infection (post-catheterization) Inferior vena cava tear Leg ulcers Thrombophlebitis Psychiatric problems Addisonian crisis after discharge
16
Our experience in the surgical management of Cushing's syndrome caused by bilateral adrenocortical hyperplasia has been reviewed. Bilateral total adrenalectomy is the treatment of choice and usually carries with it low mortality and morbidity. Although there is the added time factor of turning the patient, the flank approach gives a more direct and more adequate exposure for a bilateral operation on the adrenal glands. The majority of the deaths occurred in the early years in patients with marked hyperadrenocorticism and severe hypertension. Careful attention must be given to steroid replacement during the operation, in the immediate postoperative period and convalescent period as well as permanently thereafter. Education of the patient concerning his disease is essential and every patient is advised to wear a bracelet indicating that he has had a bilateral total adrenalectomy.
THE JOURNAL OF UROLOGY
Copyright © 1973 by The Williams & Wilkins Co.
Printed in U.S.A.
SURGICAL TREATMENT OF ADRENOCORTICAL HYPERPLASIA: 20-YEAR EXPERIENCE ALAN H. BENNETT, JOHN P. CAIN, ROBERT G. DLUHY, WILLIAM V. TYNES, J. HARTWELL HARRISON AND GEORGE W. THORN From the Departments of Surgery and Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts '
In 1912 and later in 1932 Cushing described a symptom complex in 13 patients with centripetal obesity, striae, diabetes mellitus, hypertension and psychiatric symptoms.' Although it was initially thought that all cases were caused by basophilic adenoma, it became evident that many were secondary to adrenal tumors, hypersecretion of pituitary adrenocorticotropin (ACTH) without pituitary tumor, ectopic production of ACTH and exogenous administration of glucocorticoids. and ACTH. Today, approximately 75 per cent of patients with endogenous Cushing's syndrome are suffering bilateral adrenal hyperplasia with hypothalamic-pituitary dysfunction. Therapy for classical bilateral adrenal hyperplasia has been directed at the pituitary and the adrenal glands. Although conventional pituitary radiation has not been satisfactory, more recent reports on the use of heavy particle radiation have been encouraging.2-• However, it is too early to assess the long-term results of heavy particle therapy. Surgical hypophysectomy produces good clinical remissions but may cause partial or total anterior and/or posterior pituitary insufficiency in addition to a significant operative mortality. Therefore, in most centers, therapy has been directed toward total or partial adrenalectomy. Analogous to subtotal thyroidectomy for the treatment of hyperthyroidism, subtotal adrenalectomy was performed in the early 1950's for treatment of bilateral hyperplasia.• Many patients later required re-exploration for recurrence of the disease. Thus, total bilateral adrenalectomy became the procedure of choice for Cushing's syndrome secondary to adrenocortical hyperplasia.
2 • 6 • 7 During the last 20 years 95 patients have. had surgical treatment for bilateral adrenal hyperplasia at the Peter Bent Brigham Hospital and they form the basis of this report. In this group of patients there are several who stand out as having unusual diagnostic and surgical problems which illustrate important pituitary-adrenocortical mterrelationshi ps.
CASE REPORTS
Case 1. A. K., a 16-year-old girl, was first seen with a long history of obesity, hirsutism, hypertension and primary amenorrhea. She underwent bilateral total adrenalectomy. Owing to a recurrence of symptoms and markedly elevated 17ketosteroids and 17-hydroxycorticoids, she underwent pituitary irradiation 4 years later. Thereafter, the patient once again became asymptomatic and steroid determinations returned to normal. However, 10 years later she noted the onset of increasing fatigability, weight gain and rounding of her face. Diagnostic study revealed a markedly elevated ACTH response with a loss of the normal diurnal variation of steroid levels. At laparotomy a mass was found in the right adnexa and frozen section revealed ectopic adrenocortical tissue. The right ovary and fallopian tube were removed with the mass of ectopic adrenal. The patient is now well 2 years following this surgical procedure without evidence of increased adrenocortical function. Case 2. C. R., a 31-year-old white woman, was first seen in 1954 with signs and symptoms of Cushing's syndrome. Chemical studies were consistent with bilateral adrenocortical hyperplasia and bilateral total adrenalectomy was done without complications. She did well for a 3-year period when increased pigmentation and visual field impairment with an enlarged sella turcica and high levels of plasma ACTH developed. 8 A 20
Accepted for publication June 6, 1972. Cushing, H.: 'l'he basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull. Johns Hopkins Hosp., 50: 137, 1932. 2 Orth, D. N. and Liddle, G. W.: Results of treatment in 108 patients with Cushing's syndrome. New Engl. J. Med., 285: 243, 1971. 3 Sosman, M. C.: Cushing's disease-pituitary basophilism. Amer. J. Roentgen., 62: 1, 1949. • Linfoot, J. A., Lawrence, J. H., Born, J. L. and Tobias, C. A.: The alpha particle or proton beam in the radiosurgery of the pituitary gland for Cushing's disease. New Engl. J. Med., 269: 597, 1963. 'Priestley, J. T., Sprague, R. G., Walters, W. and Salassa, R.: Subtotal adrenalectomy for Cushing's syndrome; preliminary report of 29 cases. Ann. Surg., 134: 464, 1951. 1
'Konnak, J. W. and Cerny, J. C.: The surgical treatment of Cushing's syndrome. J. Urol., 102: 653, 1969. 7 Egdahl, R. H. and Melby, J. C.: Recurrent Cushing's disease and intermittent functional adrenal cortical insufficiency following subtotal adrenalectomy. Ann. Surg., 166: 586, 1967. • Nelson, D. H., Meakin, J. W. and Thorn, G. W.: ACTH-producing pituitary tumors following adrenalectomy for Cushing's syndrome. Ann. Intern. Med., 52: 560, 1960. 321
322
BENNETT AND ASSOCIATES
gm. chromophobe adenoma of the pituitary was removed. Comment: Ten cases of pituitary adenoma have been found in this series, manifesting themselves from 1 to 13 years following surgical removal of the adrenal glands. Case 3. M. C., a 47-year-old female lawyer, was initially seen in 1947 with classical Cushing's syndrome. She underwent pituitary irradiation and had marked improvement for approximately 1 year when many signs and symptoms of Cushing's syndrome recurred. She underwent left adrenalectomy; the gland appeared somewhat small but showed some evidence of hyperplasia on pathological examination. Two weeks later, because of no change in the clinical picture or the steroid levels, the right side was explored and a 3.0 cm. adenoma was discovered, the obvious cause for Cushing's syndrome. Comment: In a recent review of experiences with adrenal tumors, 15 cases of adenoma causing Cushing's syndrome were found. 9 In 4 patients the differential between adrenocortical hyperplasia or adenoma was not made until surgical exploration. Case 4. B. P. is a typical example of a recurrence of Cushing's syndrome following subtotal adrenalectomy. She had hypertension, weight gain, striae and several other symptoms of Cushing's syndrome in 1953 at the age of 44 years. She underwent bilateral subtotal adrenalectomy in 1954 and did well for 13 years when hypertension recurred as well as other signs and symptoms of Cushing's syndrome. Chemical studies revealed increased 17-hydroxycorticoid and 17-ketosteroid excretion. Bilateral remnant adrenalectomy revealed 4 gm. tissue on the left side and 3.6 gm. on the right side. Pathologic examination revealed cortical hyperplasia. During the 4 years following the last procedure the woman has been asymptomatic. Comment: Seven patients in the entire group had remnant adrenalectomy for recurrent symptoms. CLINICAL FEATURES OF HYPERADRENOCORTICISM OWING TO HYPERPLASIA
Of the 95 patients who had adrenal operations for treatment of Cushing's syndrome secondary to bilateral adrenal hyperplasia, the mean age was 32.2 years with a 2 to 1 ratio of female to male subjects. The diagnosis of excessive glucocorticoid secretion was made on clinical (table 1) and biochemical grounds. In 76 per cent of the patients classical symptoms of Cushing's syndrome, including centripetal obesity, hirsutism, hypertension, carbohydrate intolerance, striae, plethora and psychiatric disturbances, were present. Three 9 Bennett, A. H., Harrison, J. H. and Thorn, G. W.: Neoplasms of the adrenal gland. J. Urol., 106: 607, 1971.
patients were suffering ectopic ACTH production and had marked signs and symptoms of excessive cortisol secretion. The biochemical diagnosis was made on the basis of increased urinary 17 -hydroxycorticoid and 17-ketosteroid determinations and failure of suppression of urinary 17-hydrocorticoid excretion to less than 3 mg. per day with 2 mg. dexamethasone per day. In some patients there was only minimal elevation of 17-hydroxycorticoid secretion but in these cases there was reversal of the normal diurnal steroid excretion pattern. Differentiation between adrenal neoplasia and hyperplasia was usually possible on the basis of high dosage dexamethasone suppression (2 mg. by mouth every 6 hours for 48 hours). In Cushing's syndrome associated with either adrenal neoplasia or bilateral hyperplasia caused by ectopic ACTH production, high dose dexamethasone did not significantly suppress urinary 17-hydroxycorticoid excretion. The use of excretory urography (IVP) had little to offer in the differentiation of hyperplasia from neoplasia (table 2). However, arteriography was useful in the localization of adrenal adenoma once the diagnosis was suspected clinically and confirmed by laboratory investigation. 4 Although adrenal venography is useful in the localization of mineralocorticoid-producing aderiomas, its use in localization of glucocorticoid adenomas was hazardous since the glands and adrenal veins tend to be extremely friable. TREATMENT
During the first 10 years a combination of treatments was used (table 3). Seven patients who had had subtotal adrenalectomy on each side were referred from other hospitals. Seven of the 13 patients who had subtotal adrenalectomies required removal of adrenal gland remnants for recurrence of their disease from 2 to 14 years following initial treatment. However, 70 of the 95 TABLE
1. Presenting features (95 pts.)
Classical Cushing's syndrome Hypertension Diabetes Osteoporosis Renal calculi Significant psychiatric problems
76 74 57 23 8
13
Ectopic ACTH syndrome: Ca oflung Ca of liver Malignant thymoma
TABLE
2. Radiological studies (95 pts.) Studies Pos./No. Pts. Studied
IVP with or without tomography abnormal
9/76
Angiography
4/6
Adrenal venography Retroperitoneal air study
1/1 1/1
323
SURGICAL TREATMENT OF ADRENOCORTICAL HYPERPLASIA
patients underwent bilateral total adrenalectomy as their primary treatment. Nine of these patients had staged adrenalectomies, all in the early 1950's; the time lapse between procedures ranged from 2 weeks to 2 years with an average of 4 months. The approach to the adrenal gland can be from the flank position, resecting the 11th or 12th rib, or with the patient prone again with resection of the 11th or 12th rib, through a transabdominal or transthoracic incision. In patients with Cushing's syndrome who have moderate to severe truncal obesity we have found the flank incision to be most beneficial as far as easy access to the adrenal gland is concerned (table 4). The panniculus of these patients when they are prone makes for a difficult approach in the posterior position. When they are turned on their side and the standard flank incision is used, the fat will fall forward and not interfere with exposure. The best possible exposure is gained through resection of the 11th rib. Particular attention must be paid to hemostasis since these patients are on high doses of steroids during the operation and in the postoperative period and are quite prone to infection and wound problems. With good exposure blood loss can be kept at a minimum. In this series the average blood replacement was 0.8 units per case with a range of O to 7 units; the 7 unit replacement occurred after injury to the inferior vena cava in 1 case. After the retroperitoneal space is entered, Gerota's fascia is incised and the upper pole of the kidney is mobilized and carefully displaced caudally, giving excellent exposure of the adrenal gland. Dissection of the gland is begun along the inferior and lateral borders. Either ties of 3 and 2-zero silk or Cushing (week) clips are used to secure blood vessels. On the right side the adrenal vein is quite short and care must be taken to secure this vessel. It is usually the last attachment before removing the gland on the right side. On the left side the gland has the propensity to extend down to the renal pedicle and care must be taken to avoid injury to the renal artery or vein. After the adrenal glands are reT ABLE
moved no drains are necessary and the wounds are closed in the standard fashion. OPERATIVE AND POSTOPERATIVE STEROID MANAGEMENT
On the day prior to operation a supplemental dose of 50 mg. cortisone acetate was commonly given intramuscularly at 7 p.m. On the day of the operation 100 mg. cortisone acetate was given intramuscularly 1 hour before the patient was taken to the operating room. During the operative procedure a continuous infusion of glucocorticoid (100 mg. hydrocortisone sodium succinate in 1,000 cc 5 per cent dextrose and saline) was administered at a rate of 10 to 15 mg. per hour. Postoperatively, 50 to 100 mg. hydrocortisone sodium succinate was distributed in the remaining intravenous solutions and 50 mg. cortisone acetate was given intramuscularly at 7 p.m. The total cortisone dose on the day of the operation was usually 300 mg. (table 5). During the next 7 days the intramuscular and intravenous cortisone was gradually tapered in 30 per cent decrements to maintenance levels (usually 37.5 mg. per day). Tapering was interrupted and cortisone dosage was increased if an important complication such as sepsis occurred. Oral steroid medications were resumed when fluids were allowed by mouth (usually 4 or 5 days postoperatively). Antacids or milk was given with all oral steroid doses. Mineralocorticoid therapy was usually begun when the total cortisone dose was less than 100 mg. Daily mineralocorticoid therapy was either desoxycorticosterone acetate (5 mg. 1 or 2 times daily) intramuscularly or 9-alpha fluorohydrocortisone (0.1 mg. 1 or 2 times daily) by mouth. Daily serum electrolytes, creatinine and body weights (if possible) were used to design the patient's dietary sodium requirements and dosage of salt-retaining hormone. PATHOLOGY
Table 6 shows the results of the pathological examination of these glands. Hyperplasia of the zona fasciculata was noted in more than 75 per
3. Treatment (95 pts.) TABLE
No. Pts. Pituitary irradiation before operation
29
Bilateral adrenalectomy (I stage) Bilateral adrenalectomy (staged)
61 9 3
Unilateral adrenalectomy and pituitary irradiation Unilateral adrenalectomy
Subtotal adrenalectomy
13
Removal of adrenal gland remnants Removal of ectopic adrenal tissue ( ovary)
TABLE
4. Approach to adrenal gland (95 pts.) Glands Removed
Flank (11th or 12th ribs) Posterior (11th or 12th ribs) Transabdominal
5. Steroid replacement in patients undergoing bilateral adrenalectomy
159 21
Day of operation Postop. day:
I 2 3 4 5 6 7
8 9 IO
* Reduced to I time daily.
Cortisone Acetate
9-Alpha Fluoro-
(mg.)
(mg. 2 times daily)
hydrocortisone
300
300 200 200 150 150 100 100 75 75 50
0.1 0.1 0.1 0.1 0.1 0.1 0.1 *
324
BENNET!' AND ASSOCIATES
cent of the cases. The average adrenal gland weighed 11.1 gm. with a range of 5.2 to 30 gm. The average weight of a normal adrenal gland is 3.5 to 5 gm., so that even when the pathological examination was normal, the gland weight was elevated in these patients.
TABLE
8. Causes of death (95 pts.)
Cardiovascular Electrolyte disturbance
Intra-abdominal hemorrhage Gastrointestinal hemorrhage Pneumonia, septic shock Pulmonary embolus Suicide
Unknown
COMPLICATIONS AND RESULTS
Major intraoperative complications were infrequent in this group of patients (table 7). Most troublesome were wound infections but the majority were superficial in nature and did not prolong hospitalization. Also during the period of postoperative high steroid administration, acute anxiety and manic reactions were frequently encountered. Five deaths occurred in the immediate postoperative period: 1 associated with severe hypokalemia in a patient with malignant thymoma, 1 with recurrent pulmonary emboli (9 days postoperatively), 1 with intra-abdominal bleeding from the operative site (1 day postoperatively), 1 of massive gastrointestinal bleeding (7 days postoperatively) and 1 septic shock complicating pneumonia (table 8). Four others died during the following year (2 of unknown causes, 1 of myocardial infarction and 1 by suicide). One died of a myocardial infarction at a later date and 12 were lost to followup. Seventy-three patients were well 2 to 20 years postoperatively although 12 were being treated for hypertension (table 9). Seven patients had experienced 1 or more addisonian crises associated with hypotension, hyponatremia and hyperkalemia that required hospitalization. Because of the occurrence of postoperative addisonian crises, a teaching program was instituted for adrenalectomized patients. Prior to discharge from the hospital patients are instructed in the fundamentals of steroid replacement therapy.
10
TABLE
9. Postoperative status (95 pts.)
Clinically well, 2 to 20 years postop. Well with hypertension Dead Lost to followup
61 12 10 12 95
Patients are instructed to automatically increase their glucocorticoid intake for stressful situations, such as febrile illness, dental extraction and so forth. Patients are also taught to administer steroid parenterally if they are vomiting or otherwise unable to take medications by mouth. Patients are discharged with a kit (containing needles, syringes and a parenteral steroid preparation) and are urged to purchase and wear a medialert bracelet, identifying them as adrenalectomized individuals. A more troublesome complication was the development of hyperpigmentation associated with sella turcica enlargement and pituitary tumor. This occurred 2 to 10 years after the initial bilateral adrenalectomy and was successfully treated with amelioration of pigmentation by surgical hypophysectomy (4 cases) and pituitary irradiation (6 cases). SUMMARY
TABLE
6. Pathology (95 pts.)
Hyperplasia zona fasciculata Normal No report (operation done elsewhere) Congested, hemorrhagic
TABLE
71 13 7
4
7. Complications of operation (95 pts.)
Wound infection (severe) Wound infection (superficial) Cerebrovascular accident Myocardial infarction Pneumonia Urinary tract infection (post-catheterization) Inferior vena cava tear Leg ulcers Thrombophlebitis Psychiatric problems Addisonian crisis after discharge
16
Our experience in the surgical management of Cushing's syndrome caused by bilateral adrenocortical hyperplasia has been reviewed. Bilateral total adrenalectomy is the treatment of choice and usually carries with it low mortality and morbidity. Although there is the added time factor of turning the patient, the flank approach gives a more direct and more adequate exposure for a bilateral operation on the adrenal glands. The majority of the deaths occurred in the early years in patients with marked hyperadrenocorticism and severe hypertension. Careful attention must be given to steroid replacement during the operation, in the immediate postoperative period and convalescent period as well as permanently thereafter. Education of the patient concerning his disease is essential and every patient is advised to wear a bracelet indicating that he has had a bilateral total adrenalectomy.