Outcome of Adrenalectomy for Cushing’s Syndrome: Experience from a Tertiary Care Center
Anand Kumar Mishra . Amit Agarwal . Sushil Gupta · G. Agarwal · A. K. Verma · S. K. Mishra
Published online: 30 May 2007 C Société Internationale de Chirurgie 2007
Abstract Adrenalectomy continues to play an important role in the management of Cushing’s syndrome (CS). Untreated CS causes considerable physical and mental morbidity and mortality. However, little information is available on the effect of adrenalectomy in ameliorating functional disabilities in CS patients. Our study assesses the long-term outcome of adrenalectomy in patients with CS. This is a retrospective analysis of CS patients managed during 1990-2005 at a tertiary care center. We analyzed the clinical presentation, endocrine evaluation, and surgical management preoperatively and following adrenalectomy. The subjects were 37 patients with CS (age 24.5 + 15 years, range 1-60 years; male:female 1.0:1.2). There were various etiologies-unilateral adrenocortical adenoma (n = 11), adrenocortical carcinoma (n = 13), pituitary ACTH- secreting adenoma with failed transsphenoidal surgery (n = 4), ectopic unidentified ACTH source (n = 7), bilateral adrenal macronodular hyperplasia (n = 1), primary pig- mented nodular adrenal hyperplasia (n = 1) -for which the patients underwent adrenalectomy: unilateral (n = 22), bilateral (n = 13), or adrenonephrectomy (n = 2). Two patients died during the perioperative period owing to chest infection and sepsis. At the median follow-up of 60 months (range 6-144 months), the patients exhibit significant persistence of obesity (41%), proximal muscle weakness (44%), menstrual irregularity (8%), hypertension (31%), and insulin-dependent diabetes (29%). Hirsutism and psy- chological abnormalities persisted to a lesser extent. All
patients had biochemical cure of CS following surgery evidenced by the 8 a.m. basal cortisol ≤ 5 µg/dl. The hypothalamic-pituitary-adrenal axis recovered as shown by normalization of the short synacthen-stimulated cortisol level (peak level ≥ 20 µg/dl) after a median follow-up of 9 months (range 6-18 months). Incomplete clinical recovery following adrenalectomy emphasizes the need of early recognition and prompt treatment of CS. Surgery for adrenocortical adenoma is safe and effective; however, survival of patients with CS due to adrenocortical carci- noma remains poor. Bilateral adrenalectomy provides early control of hypercortisolism in selected cases of unlocalized ectopic ACTH syndrome or failed transsphenoidal surgery. Even though functional recovery is incomplete after adre- nalectomy, quality of life improves considerably.
Introduction
Endogenous CS is a consequence of prolonged and sus- tained pathologic hypercortisolism. The clinical features more specific for CS include centripetal fat distribution, proximal myopathy, wide purple striae, osteoporosis, and decreased linear growth with continued weight gain in a child. Approximately 85% of CS patients are corticotropin- dependent [pituitary adenoma or ectopic adrenocortico- tropic hormone (ACTH) syndrome], and 15% are cortico- tropin-independent, caused by adrenal lesions (adenoma, carcinoma) and rarely by primary bilateral adrenal hyper- plasia.
Untreated CS causes significant physical and functional disability and is often fatal if untreated. During the early 1950s Plotz et al. [1] demonstrated a 5-year survival of only 50% among untreated patients. According to Ross and
A. K. Mishra . A. Agarwal () · S. Gupta ·
G. Agarwal · A. K. Verma · S. K. Mishra Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow 226 014, India
e-mail: amit@sgpgi.ac.in
Linch [2], the mortality rate of treated CS patients was still four times greater than that of the baseline population. Following cure of hypercortisolism, clinical recovery is slow and incomplete, but long-term outcome data are limited. The causes of disability are the complications of osteoporosis, proximal myopathy, depression, and other psychiatric symptoms. There is an improvement in bone mineral density (BMD) in treated CS patients [3], but BMD normalization takes 1 to 2 years. Lost functional ability is regained, but the process is slow, taking 6 to 30 months [4- 6].
The objective of this retrospective study was to assess the long-term outcome of patients after adrenalectomy for CS as no data on the outcome of CS in an Indian population have been published.
Materials and methods
A total of 37 consecutive patients with clinical and bio- chemical evidence of CS underwent adrenalectomy be- tween January 1990 and December 2005. Our patients included those with adrenocortical adenomas, adrenocor- tical carcinomas, an unlocalized ectopic ACTH source, Cushing’s disease with failed transsphenoidal surgery (TSS), and primary adrenal hyperplasia. The diagnosis of CS was established based on a typical clinical presentation and an endocrine evaluation (Fig. 1).
All patients underwent adrenalectomy utilizing the anterior transperitoneal route. Operative findings, tumor size, and weight were recorded in each case. All patients were given perioperative steroid supplementation (Ta- ble 1). Patients were discharged after stitch removal (usu- ally 10 days) and when their postoperative drug requirements were stabilized (glucocorticoids, mineralo- corticoids, and/or antihypertensives). The first postopera- tive visit occurred 3 weeks after discharge, followed by visits at about 3, 5, 12, and 18 months. During follow-up we performed a short synecthen test, serum basal cortisol (8 a.m.) assay, and radiologic tests wherever appropriate. Follow-up was ensured through correspondence and tele- phone conversations. Successful treatment was defined as normalization of the hypothalamic-pituitary-adrenal (HPA) axis and disappearance of symptoms.
Results
The age range of our patients was 1 to 60 years (mean 24.5 ± 15.0 years) with a female/male ratio of 1.2:1.0. The etiopathology of all CS cases is shown in Table 2. Post- operative complications were observed in 10 patients: wound complications in 5, chest infections in 4, and a fecal
Clinical suspicion of Cushing’s syndrome
4
(Screening test)
24 Hr Urine free cortisol OR
Overnight Dexamethasone suppression test
(1mg Dexamethasone at 11pm: S.cortisol 8 AM >5ug/dl)
4 (Confirmatory test) Low dose Dexamethasone Suppression test (0.5mg Dexamethasone q6h X 2days: 3rd day S.cortisol 8 AM >5ug/dl)
4
Diagnosis of CS confirmed: Differential diagnosis
· 11pm plasma ACTH (pg/ml)
- < 10: ACTH independent tumor (Adrenal Cause)
- 10- 20: Inconclusive
- >20 ACTH dependent tumor (Pituitary or Ectopic ACTH cause)
· High dose Dexamethasone Suppression test for basal S. Cortisol 8 AM suppression (HDDST-2mg 6h X 2 day)
- suppression of S. Cortisol >50% of basal cortisol 8AM suggest Pituitary- Cushing’s disease
- < 50% (Non- suppressible): Adrenal / Ectopic ACTH secreting tumor
4
Imaging: US / MRI / CT abdomen, chest, neck as appropriate
Inferior petrosal sinus sampling was performed when HDDST was >50% suppressible but MRI sella failed to identify pituitary adenoma.
!
Pre-operative preparation:
· Vigorous chest physiotherapy
· Prophylactic therapy for Venous thromboembolism
· Electrolyte correction
· Control: BP, Glucose, Electrolytes
· Prophylactic antibiotics / Antifungal therapy as and when required
1
Adrenalectomy: Unilateral/ bilateral depending on etiology (Open / Laparoscopic) Peri-operative Steroid supplementation
1
Follow up: 3 weeks, 3 and 6 months, 12 and 18 months and then annually
Clinical / Functional assessment, biochemical recovery of Hypothalmic -Pitutary axis
Fig. 1 Protocol for diagnosis and management of Cushing’s syn- drome
fistula in 1. There were two perioperative deaths; both patients died because of severe chest infection and sepsis.
Table 3 shows clinical features of the patients before and after adrenalectomy. All patients were cured bio- chemically as assessed by the basal plasma cortisol assay; and the HPA axis normalized during a median follow-up of 9 months (range 6-18 months). However, at a median 60-month follow-up (range 6-144 months) 11 (29.7%)
Springer
| Time after operation (days) | IV steroids | Oral steroids | Oral fludrocortisone (mg/day) |
|---|---|---|---|
| Day of operation | 30 mg/ hr × 6 hr then 10 mg/hr × 18 hr | — | — |
| +1 | 200 mg/24 hr | Nil | Nil |
| +2 | 100 mg/24 hr | 20 mg q 6 hr | Nil |
| +3 | Nil | 25 mg q 6 hr | 0.1 |
| +4 to +7 | Nil | 20 mg q 6 hr | 0.1 |
| +8 to +10 | Nil | 20 mg q 8 hr | 0.1 |
| +11 to +14 | Nil | 10 mg q 6 hr | 0.1 |
| +15 onward | Nil | 10 mg q 8 hr | 0.1 |
| Etiology (n = 37) | No. |
|---|---|
| ACTH-dependent | |
| Failed pituitary TSS surgery | 4 (10.8%) |
| Ectopic ACTH source unclear/tumor not found | 7 (18.9%) |
| ACTH independent | |
| Unilateral adrenal adenoma | 11 (29.7%) |
| Adrenal carcinoma | 13 (35.1%) |
| Primary pigmented nodular hyperplasia | 1 (2.7%) |
| Bilateral macronodular adrenal hyperplasia | 1 (2.7%) |
Bilateral adrenalectomy (n = 13, 35.1% ) was performed in the ACTH-dependent group (n =11) and in the bilateral macronodular and primary pigmented adrenal hyperplasia group (n = 2)
ACTH: adrenocorticotropic hormone; TSS: transsphenoidal surgery
patients had died. Patients with adrenocortical carcinoma who were lost to follow-up at 12 months after surgery were removed from the survival data calculation. The causes of deaths are shown in Table 4. Overall outcome of all groups of patients is summarized in Table 5. We carried out a subgroup analysis based on etiology.
Adrenocortical adenoma
There were 11 patients (2 males, 9 females) with adreno- cortical adenoma at a mean age of 27.95 ± 16.42 years. There were four right-side and seven left-side tumors. Ten patients underwent adrenalectomy via the transperitoneal approach, and one underwent laparoscopic adrenalectomy. One 29-year-old woman presented during the second tri- mester of pregnancy with uncontrolled hypertension, dia- betes, and thrombocytopenia. She underwent hysterotomy and left adrenalectomy simultaneously under a one-time transfusion of multiple packs of platelets from multiple donors. This patient had delayed recovery of the HPA axis at 18 months and conceived 22 months after surgery. She had an uneventful pregnancy. All patients received peri-
operative steroid supplementation as per the protocol of the department (Table 1). All other patients had recovery of the HPA axis at 6 to 18 months. All patients were alive at the median follow-up of 66 months.
Adrenocortical carcinoma
There were 13 patients (6 males, 7 females) with adreno- cortical carcinomas at a mean age of 17.08 ± 13.56 years. None of these patients had evidence of distant metastases at the time of presentation. All patients underwent surgery through an open transperitoneal route (10 for adrenalec- tomy, 1 for adrenalectomy + splenectomy, 2 for adrenal- nephrectomy). All patients had gross resection of the tu- mor, and operation was considered potentially curative. The mean tumor weight and size were 527 g (24-1500 g) and 14.4 cm (6-22 cm), respectively. All patients received glucocorticoid supplementation as per the protocol of the department (Table 1). Eleven patients also received adju- vant treatment: locoregional radiotherapy in four, mitotane in one, locoregional radiotherapy + mitotane in one, and ketoconazole-only in five. Although all patients had bio- chemical recovery and considerable clinical recovery, survival was dismal, with only two patients alive at a median follow-up of 18 months. The longest survival (30 months) was seen in the patient who received adjuvant locoregional radiotherapy and mitotane.
Bilateral adrenalectomy for unlocalized source
In seven patients (five males, two females) with a con- firmed diagnosis of CS, there was no identifiable source of ACTH producing the tumor. Their mean age was 30.13 ± 9.19 years. The serum ACTH level was > 20 pg/ml in five patients (mean 54 pg/ml, range 34-449 pg/ml), and two patients had levels between 10 to 20 pg/ml. All pa- tients underwent a high-dose dexamethasone suppression test; and all were evaluated by chest radiography, abdominal computed tomography (CT), high-resolution
| Signs/symptoms | Plotz [1] 1952 (n = 33) | Soffer [7] 1961 (n = 50) | Urbanic [8] 1981 (n = 31) | Ross [2] 1982 (n = 70) | Present series (n = 33 before surgery) | Present series (n = 33 after surgery) |
|---|---|---|---|---|---|---|
| Obesity or weight gain | 97 | 86 | 79 | 97 | 92 | 41 |
| Hypertension | 84 | 88 | 77 | 74 | 59 | 31 |
| Abnormal glucose | 94 | 84 | 39 | 50 | 38 | 29 |
| tolerance | ||||||
| Weakness (PMW) | 83 | 58 | 90 | 56 | 82 | 44 |
| Hirsutism | 73 | 84 | 64 | 81 | 41 | — |
| Androgen excess | 82 | - | 35 | 21 | 28 (clitoromegaly 4) | — |
| Menstrual changes | 86 | 72 | 69 | 84 | 28 | 8 |
| Osteopenia/ | 83 | 56 | 48 | 50 | 69/10 | — |
| fracture | ||||||
| Ecchymoses | 60 | 68 | 77 | 62 | 69 | — |
| Striae | 60 | 50 | 51 | 56 | 82 | — |
Results are percents
PMW: proximal muscle weakness
Obesity was defined as body mass index > 25%
Proximal muscle weakness during follow-up was assessed by objective clinical assessment
| Patient/age/sex | Etiology | Cause of death |
|---|---|---|
| D./6/F | AC | Died 12 months postop: liver and lung metastases |
| K./6/F | AC | Died 14 months postop: liver metastases |
| I./14/M | AC | Perioperative death cause: chest infection sepsis, MOF |
| G.P./30 /M | AC | Died 30 months postop: liver and lung metastases |
| M.S./12/M | AC | Died 9 months postop: local and lung metastases |
| M.K./32/F | AC | Died 11 months postop: liver metastases |
| B.S./16/M | AC | Died 14 months postop |
| A.K.V./37/M | Unlocalized source | Died 2 months postop: with military pulmonary tuberculosis |
| V.S./26/M | Unlocalized source | Postop acute respiratory distress syndrome, sepsis, intracerebral hemorrhage |
| P.L./6/M | PPNAD | Died 9 months postop with addisonian crisis after diarrhea |
| R.S.V./60/ M | Macronodular hyperplasia | Died 2.5 months postop with chest infection, sepsis, intracerebral hemorrhage |
AC: adrenal carcinoma; PPNAD: primary pigmented nodular hyperplasia; MOF: multiple organ failure
CT or magnetic resonance imaging (MRI) of the chest, and pituitary MRI. However, no ectopic source of ACTH secretion could be identified. Two patients had undergone inferior petrosal sinus sampling (IPSS), but there was no central to peripheral gradient. A 34-year-old woman was diagnosed with a thymic lesion on mediastinal CT and underwent thymectomy. She was not cured; and after 14 months she underwent bilateral (B/L) adrenalectomy to control severe hypercortisolism. All patients underwent simultaneous B/L adrenalectomy via the anterior trans- peritoneal approach.
There was one perioperative death because of postop- erative acute respiratory distress syndrome, sepsis, and intracerebral hemorrhage; and one patient died 3 months
after surgery because of chest infection. He was suffering with miliary tuberculosis preoperatively. All patients re- ceived lifelong steroid supplementation as per the protocol of the department (Table 1). All five patients had bio- chemical and clinical recovery with no evidence of tumor during the median follow-up of 42 months.
B/L adrenalectomy for failed TSS
There were four patients (two males, two females) who underwent B/L adrenalectomy for failed TSS for a pituitary adenoma at a mean age of 21.6 + 6.1 years. The first patient had failed TSS from another hospital and had persistent symptoms. She was referred to us for B/L adrenalectomy 8
| Table 5 Outcome of all groups of patients | ||||
|---|---|---|---|---|
| Etiology | No. | Early outcome ( ≤ I year) | Late outcome (> 1 year) | Disease-specific mortality |
| Adenoma | 11 (27.5%) | Cured | No mortality | None |
| Median follow-up 66 months H-P recovery: 10 (9-18 months) All alive and well No evidence of disease | ||||
| Carcinoma | 13 (32.5%) | Death: 3 (postop day 5, and 9 and 11 months) | Median follow-up: 18 months Death: 4 (12, 14, 14, 30 months) Lost to follow-up: 4 | 6 (46.15%) |
| Alive: 2 | ||||
| Unlocalized source of excess hormone | 7 (17.5%) | Death: 2 (postop day 13, and 2 months) | Median follow-up: 42 months Biochemical and clinical recovery All other alive and well Steroid supplementation | None |
| No evidence of tumor or Nelson's syndrome | ||||
| Failed pituitary surgery (TSS) | 4 (10%) | Alive | Median follow-up 14.5 months Alive | None |
| Steroid supplementation No evidence of tumor or Nelson's syndrome | ||||
| Hyperplasia: PPNAD/ macronodular | 2 (5%) | Death: 2 (2.5 and 9 months ) | — | 1 (50%) |
years after the pituitary surgery. She is alive and well at 48 months of follow-up with no evidence of Nelson’s syn- drome.
The second patient was a 16 years old boy who had a hypodense lesion in the pituitary gland on MRI, and IPSS revealed a central to peripheral gradient (left 600.2 pg/ml, right 69.7 pg/ml, peripheral 62.0 pg/ml). On the fifth day following TSS, the serum cortisol level was high (1096 nmol/L). He was prescribed ketoconazole (800 mg/day), but within 2 months of surgery he developed severe backache and became bedridden. His lumbosacral spine radiograph showed evidence of a osteoporotic compressive fracture of L3. In view of his severe and crippling hyper- cortisolism, B/L adrenalectomy was performed. The his- topathology was reported as B/L nodular adrenal hyperplasia. He had complete biochemical and clinical recovery. During the 22-month follow-up, there has been no evidence of Nelson’s syndrome or recurrence. He is able to carry out his normal daily activities and continues to attend school.
The other two patients also had TSS at another hospital and were referred to us after persistence of symptoms. They underwent B/L adrenalectomy in view of their young age and severe symptoms. Both patients are alive and well 7 and 4 months after surgery, respectively.
Primary adrenal hyperplasia
The first patient was a 9-year-old child who underwent B/L adrenalectomy for primary pigmented nodular adrenal hyperplasia. Although he had biochemical cure and clinical recovery, he died 9 months after surgery because of an addisonian crisis following an episode of diarrhea at his village.
The second patient was a 60-year-old man who had CS with a past history of a cerebrovascular accident and right hemiparesis. He was diagnosed as having B/L adrenal macronodular hyperplasia. He underwent transperitoneal simultaneous B/L adrenalectomy. During the surgery the patient had unexplained hypotension, and after surgery he could not be extubated. On the MRI brain scan there was evidence of a rebleed and global hypoxia. The patient died 2.5 months later with sepsis and multiorgan failure.
Discussion
The management of CS has evolved considerably over the last four decades. During the 1950s “blind” ablation of the target organ (e.g .. , subtotal adrenalectomy, bilateral adre- nalectomy) was the treatment of choice. Over the years, the
therapeutic strategy has shifted to a more tailored treatment of the primary problem. Adrenalectomy continues to play an important role in the treatment of CS and is the treat- ment of choice for an adrenal adenoma, adrenocortical carcinoma, and bilateral primary cortical hyperplasia. With recognition of the pituitary origin of CS and the develop- ment of TSS during the 1970s, bilateral adrenalectomy became a secondary operation reserved for patients whose treatment failed after the transsphenoidal technique. Fur- thermore, in selected cases, bilateral adrenalectomy con- tinued to be the appropriate treatment of either Cushing’s disease or the ectopic ACTH syndrome where ACTH- secreting tumors remain unlocalized.
It may appear as if we are dealing with a diffuse group of diseases; however, the common link is the adrenal gland, at which the therapy is directed. We reemphasize the sig- nificant role of adrenalectomy in patients with hypercorti- solemia irrespective of etiology, especially in view of its minimal morbidity and mortality, reflecting the improve- ments in preoperative control of hypercortisolemia, surgi- cal techniques, and anesthesia.
After adrenalectomy, patients are followed up to assess biochemical and clinical recovery because it is well known that after successful treatment clinical recovery is slower than the biochemical recovery. Biochemical recovery is assessed by the short synacthen test. Complete recovery of the HPA axis takes 1 to 2 years. Unfortunately, osteopo- rotic fractures, fatigue, weakness, and persisting mental problems have led to permanent disability.
The signs and symptoms of CS reported in four major series are compared with our patients in Table 3. Although the clinical presentation is similar between Indian and Western patients, our patients had fewer incidences of hypertension and abnormal glucose tolerance. Also, the incidence of fracture was 10% in our series, which has not been reported in other series. All of our patients had bio- chemical recovery, whereas the clinical recovery was incomplete (Table 3). Persistence of obesity after surgery was observed in 41% of our patients, which is possibly due to underlying obesity or failure to lose weight after hyper- cortisolemia correction. Persistence of disabling proximal muscle weakness after hypercortisolemia correction was observed in 38%, and this is disturbing. It may be attributed to ethnic variation in steroid metabolism, or it could be aggravated by associated osteomalacia, as vitamin D defi- ciency is rampant in the Indian population [9, 10]. Gluco- corticoid supplementation may be another factor influencing the clinical recovery, as supranormal supplementation could hamper it. This clinical recovery was seen over a median follow-up of 60 months (range 6-144 months) of all groups of patients. Recovery of the HPA axis in the adrenal ade- noma group took 6 to 18 months. Clinical recovery of pa- tients with adrenocortical carcinoma could not be assessed,
as these patients had a short survival (18 months). Adre- nalectomy greatly benefited patients with adenoma or unlocalized ACTH-producing tumors and failed TSS pa- tients. We could not assess the recovery of osteopenia, as bone mineral density was not measured during follow-up; however 10% patients with greenstick fractures had com- plete healing during the follow-up. There is a varied pattern of clinical recovery in our patients, and the probable reason is the heterogeneous presentation in the various groups. We believe that the clinical recovery pattern could be assessed only in a prospective controlled study, but this would be difficult to carry out in view of rarity of this disease.
Ross et al. [11] evaluated the clinical response in 57 adult patients with CS due to bilateral adrenocortical hyperplasia or adrenocortical adenoma. Despite satisfac- tory biochemical remission of the disease, the clinical re- sult was far less acceptable. There was persistence of obesity (55%), menstrual irregularity (41%), hypertension (29%), and insulin-dependent diabetes (22%).
Iacobone et al. [12] studied 50 patients with ACTH- independent hypercortisolism treated by unilateral adre- nalectomy during a mean follow-up of 134 months. They observed 100% biochemical recovery, but obesity and hypertension recovered in only 59.6% and 57.55%, respectively.
Grabner et al. [5] reported that 24% of the patients with Cushing’s disease treated by adrenalectomy were unable to return to work. Pikkarainen et al. [13] studied 74 patients and found that 46% of the surviving patients stated that they felt fully recovered from the disease; 19% were unable to return to work and subsequently retired because of dis- ability. Altogether, 76% complained of persisting fatigue after successful treatment. Proximal muscle weakness was reported by 32% of the patients, and 18% had persistence of menstrual disorders.
In the Mayo Clinic series [14] of 50 patients who had undergone B/L adrenalectomy, the 5-year survival was 100% for patients with adrenal hyperplasia, 86% for pa- tients with Cushing’s disease, and 39% for patients with ectopic ACTH production. They observed a high incidence of chronic physical complaints (chronic fatigue 60%, symptom-free 30%) and considered it a reflection of residual sequelae of chronic Cushing’s syndrome.
In patients with Cushing’s disease who undergo B/L adrenalectomy, two risk factors have been associated with the occurrence of Nelson’s syndrome (dark skin pigmenta- tion, very high corticotropin concentrations, radiologic evi- dence of pituitary adenoma): high pretreatment urinary cortisol and the presence of pituitary adenoma [15]. In our experience, none of the patients who underwent B/L adre- nalectomy for failed pituitary surgery developed Nelson’s syndrome perhaps due to the short follow-up. It is surprising that three patients who underwent TSS with evidence of
pituitary adenoma on histopathology showed persistent hy- percortisolemia. Nagesser et al. [16], in a study of 44 patients undergoing B/L adrenalectomy for Cushing’s disease, con- cluded that B/L adrenalectomy remains the final treatment for Cushing’s disease. They emphasized the need for con- tinued regular long-term follow-up to diagnose recurrent disease and the development of Nelson’s syndrome.
Quality of life after surgery is also an important issue. These patients may be seriously compromised even when they are apparently doing well in hormonal terms with replacement therapy [17] during the follow-up. This dis- order has profound physical and emotional effects, and full recovery may be slow. The speed with which psychoso- matic recovery occurs may depend on various factors, such as properly individualized glucocorticoid and other hor- mone replacement (when indicated). Assessment of psy- chological well-being and functional capacity should therefore be added to traditional hormonal and clinical variables [18]. Pikkarainen et al. [13] studied quality of life by a questionnaire method; 56% of the patients reported depression prior to therapy for CS, and 34% of the recovered patients reported depression at the time of completing the questionnaire. In the present study, we could not assess the quality of life during follow-up as the study was performed retrospectively.
Mortality among CS patients resulted mostly from infection and cerebrovascular disease. Survival of patients who have CS associated with malignancy, including adrenocortical carcinomas, remains extremely poor. One patient died perioperatively after adrenalectomy because of severe chest infection and sepsis, and six patients died 9, 11, 12, 14, 14, and 30 months after surgery with adreno- cortical carcinoma. Among those with an unlocalized ACTH-secreting tumor, there was one perioperative death because of postoperative acute respiratory distress syn- drome, sepsis, and intracerebral hemorrhage; and one pa- tient died 3 months after surgery because of chest infection following miliary tuberculosis. Two patients with bilateral nodular hyperplasia of the adrenal gland died 2.5 months and 9.0 months postoperatively. A 9-year-old child with pigmented nodular hyperplasia died 9 months after surgery owing to an addisonian crisis after an episode of diarrhea at his village. We believe that the deaths due to an addisonian crisis and to miliary tuberculosis were preventable. In our country, there is poor access to health care in remote areas, compromising prompt referral to a hospital in an emer- gency. Compliance from rural background patients for regular follow-up is difficult as well because of the pre- vailing low literacy rate and socioeconomic conditions.
Other centers have also reported high mortality of CS patients after surgery. In the Nogoya series [19] five adre- nocortical carcinoma patients and four with ectopic ACTH syndrome died within 2 years after operation. Welbourn [20]
found decreased long-term survival in patients after total adrenalectomy for Cushing’s disease. A Danish population- based study [21] over an 11-year follow-up concluded that CS is associated with increased mortality among patients with no concurrent malignancy, and the excess mortality was mainly observed during the first year of the disease.
Conclusion
Our results emphasize the fact that patients of CS after adrenalectomy require long-term health and social surveil- lance, even after biochemical cure. They need to be treated using a team approach for best results. Various features indicating recovery should be sought before and after treatment. Glucocorticoid replacement after adrenalectomy should be individualized to improve the quality of life.
We thus conclude that (1) survival of patients with Cushing’s syndrome associated with adrenocortical carci- nomas remains extremely poor; (2) adrenalectomy for adrenal adenoma can be performed with zero mortality; and (3) bilateral adrenalectomy provides early control of severe hypercortisolism in selected cases of failed TSS and an unlocalized ACTH source. Even though functional recovery may be incomplete after B/L adrenalectomy, quality of life does improve considerably.
References
1. Plotz RM, Knowlton AI, Ragan C (1952) The natural history of Cushing’s syndrome. Am J Med 13:597-614
2. Ross E, Linch D (1982) Cushing’s syndrome-killing disease: discriminatory value of signs and symptoms aiding early diag- nosis. Lancet 2:646-649
3. Manning PJ, Evans MC, Reid IR (1992) Normal bone mineral density following cure of Cushing’s syndrome. Clin Endocrinol (Oxf) 36:229-234
4. Welbourn RB, Montgomery DA, Kennedy TL (1971) The natural history of treated Cushing’s syndrome. Br J Surg 58:1-16
5. Grabner P, Hauer-Jensen M, Jervell J, et al. (1991) Long term results of treatment of Cushing’s disease by adrenalectomy. Eur J Surg 157:461-464
6. Gotch P (1994) Cushing’s syndrome from the patient’s perspec- tive. Endocrinol Metab Clin North Am 23:607-617
7. Soffer LJ, Iannaccone A, Gabrilove JL (1961) Cushing’s syn- drome: a study of fifty patients. Am J Med 300:129-135
8. Urabinic RC, George JM (1981) Cushing’s disease: 18 years’ experience. Medicine 60:14-24
9. Arya V, Bhambri R, Godbole MM, et al. (2004) Vitamin D status and its relationship with bone mineral density in healthy Asian Indians. Osteoporos Int 15:56-61
10. Glerup H, Mikkelsen K, Poulsen L, et al. (2000) Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 66:419-424
11. Ross EJ, Linch DC (1985) The clinical response to treatment in adult Cushing’s syndrome following remission of hypercortiso- laemia. Postgrad Med J 61:205-211
12. Iacobone M, Mantero F, Basso Sm, et al. (2005) Results of long term follow up after unilateral adrenalectomy for ACTH inde- pendent hypercortisolism in series of fifty patients. J Endocrinol Invest 28:327-332
13. Pikkarainen L, Sane T, Reunanen A (1999) The survival and well-being of patients treated for Cushing’s syndrome. J Intern Med 245:463-468
14. O’Riordain DS, Farley DR, Young WF Jr, et al. (1994) Long term outcome of bilateral adrenalectomy in patients with cushing’s syndrome. Surgery 116:1088-1093
15. Boscaro M, Barzon L, Fallo F, et al. (2001) Cushing’s syndrome. Lancet 357:783-791
16. Nagesser SK, van Seters AP, Kievit J, et al. (2000) Long-term results of total adrenalectomy for Cushing’s disease. World J Surg 24:108-113
17. Sonino N, Fava GA (1998) Psychosomatic aspects of Cushing’s disease. Psychother Psychosom 67:140-146
18. Sonino N, Boscaro M, Fallo F, et al. (2000) A clinical index for rating severity in Cushing’s syndrome. Psychother Psychosom 69:216-220
19. Imai T, Funahashi H, Tanaka Y, et al. (1996) Adrenalectomy for treatment of Cushing syndrome: results in 122 patients and long- term follow-up studies. World J Surg. 20:781-786; discussion 786-787
20. Welbourn RB (1985) Survival and causes of death after adre- nalectomy for Cushing’s disease. Surgery 97:16-20
21. Lindholm J, Juul S, Jorgensen JOL, et al. (2001) Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 86:117-123