ENDOCRINE SURGERY
ANZJSurg.com
Reoperative adrenal surgery: lessons learnt
Charles T. Tan, Goswin Y. Meyer-Rochow, Mark S. Sywak, Leigh W. Delbridge and Stan B. Sidhu Endocrine Surgical Unit, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
Key words
adrenal, reoperative, tumour.
Abbreviations
ACC, adrenal cortical carcinoma; CT, computed tomography; MEN, multiple endocrine neoplasia; MIBG, meta-iodobenzylguanidine; PET, positron emission tomography; RET, rearranged during transfection proto-oncogene; SDHB, succinate dehydrogenase subunit B; SDHD, succinate dehydrogenase subunit D; VHL von Hippel Lindau.
Correspondence
Assoc. Professor Stan B. Sidhu, Endocrine Surgical Unit, Royal North Shore Hospital, University of Sydney, St Leonards, NSW 2065, Australia. Email: stansidhu@nebsc.com.au
C. T. K. Tan MB ChB, FRCS; G. Y. Meyer-Rochow FRACS; M. S. Sywak MB BS, FRACS; L. W. Delbridge MD, FRACS; S. B. Sidhu PhD, FRACS.
Accepted for publication 25 July 2008.
doi: 10.1111/j.1445-2197.2009.04892.x
With the widespread use of abdominal imaging, the detection and therefore incidence of adrenal tumours is increasing. The laparoscopic approach to primary surgical resection of adrenal tumours has now become the standard of care. There is scarce published literature regarding the management and outcomes of recurrent adrenal tumours. The aim of the present study was therefore to review the authors’ experience with reoperative adrenal surgery. A retrospective review of reoperative adrenalectomy cases identified from the prospectively maintained University of Sydney Endocrine Surgical Unit Database from January 1988 to July 2007 was carried out. There were nine (3.5%) reoperative adrenalectomies in six patients. Two were cases of adreno- cortical carcinoma, two involved cases of familial phaeochromocytomas and two cases were due to sporadic phaeochromocytomas. Reoperative adrenal surgery is an uncom- mon event. During the index surgery for adrenal tumours, all adrenal tissue should be removed and knowledge of the vagaries of adrenal anatomy is essential. Reoperative adrenal surgery is a safe procedure and may confer survival benefit or symptom relief. Lifelong follow up is essential for all patients who have had surgery for functional and malignant adrenal tumours.
Introduction
Adrenal tumours were previously believed to be uncommon, but with the widespread use of abdominal imaging the incidence is now as high as 7% in patients over the age of 70 years.1 Indications for surgery include functioning adrenocortical tumours (Cushing’s syn- drome caused by a benign cortisol-producing adenoma, Conn’s syn- drome from an aldosterone-producing adenoma or a virilizing/ feminizing secreting tumour), functioning adrenomedullary adrenal tumours (phaeochromocytoma) and non-functioning adrenal tumours, which may be benign or malignant. Historically, open adrenal surgery was the mainstay of treatment for these tumours. The laparoscopic approach to surgical resection of adrenal tumours, either transperitoneal or retroperitoneal, has now become the stan- dard of care.2,3
Reoperative adrenal surgery is uncommon and there are few pub- lications regarding this topic in the literature. The aim of the present study was to review our experience with reoperative adrenal surgery,
in particular to determine if there were any identifiable factors that may have contributed to need for reoperation and to determine whether there is an increase in morbidity or mortality associated with reoperative adrenal surgery.
Methods
We performed a retrospective review of reoperative adrenalectomy cases identified from the prospectively maintained University of Sydney Endocrine Surgical Unit database from January 1988 to July 2007. All patients who had an adrenalectomy for an adrenal tumour were included. Data on patient characteristics, signs and symptoms at presentation, clinical evidence of hormone production, radio- graphic and histopathologic tumour size, type of surgery, morbidity and mortality postoperatively of both the index (if performed at Royal North Shore Hospital) and reoperation were extracted from the records.
Results
In the 19 years between January 1988 and July 2007, 260 adrena- lectomies were performed, of which 175 were laparoscopic and 85 were open. Of those in the laparoscopic group, 170 had adrenalec- tomy via the anterior transperitoneal approach and five by the ret- roperitoneal approach. In the open surgery group, 36 patients had adrenalectomy via the anterior approach and 49 via the posterior approach. There were 160 female and 100 male patients. The mean age of the patients was 51.6 years (range, 14-83 years). One hundred and seventy-two (66%) of the patients had surgery for functioning tumours, of which 80 had Conn’s syndrome, 31 had Cushing’s syndrome, 60 had phaeochromocytomas and one had a virilizing tumour. Sixty-eight patients (26%) had surgery for benign inciden- talomas and 20 (8%) for cancer. Fifteen of the malignant tumours were primary adrenal cortical carcinoma (ACC) and the other five were metastasis to the adrenal gland. The mean size of the tumours removed was 3.4 cm (range, 1.0-10.0 cm). There were nine (3.5%) reoperative adrenalectomies in six patients. The characteristics of the six patients are summarized in Table 1.
Case 1
A 17-year-old woman presented with a mixed cortisol-virilizing tumour. Her preoperative computed tomography (CT) imaging dem- onstrated a heterogenous nodular bi-lobed 4-cm mass with periph- eral enhancement and low attenuation centrally (Fig. 1). This patient underwent laparoscopic adrenalectomy at another hospital in July 2005 with the histology demonstrating an ACC. The histopathology demonstrated rupture of the tumour capsule, which was believed to have occurred as the tumour was extracted through the abdominal wall in an endocatch bag at the time of her index surgery.
After recovery from her initial procedure, her biochemical profile normalized. Postoperative CT demonstrated residual adrenal tissue sitting behind a surgical clip (Fig. 2). This was confirmed by the primary surgeon, who described how he had placed a clip across the normal adrenal gland. Whole-body CT and positron emission tomography (PET) ruled out further metastatic disease. At this point, with the diagnosis of carcinoma and presence of residual adrenal tissue in the tumour bed and after a multi-disciplinary consensus, the
patient underwent an open completion adrenalectomy and retroperi- toneal clearance in November 2005. The histopathology indicated residual adrenal gland and peri-adrenal fat with no evidence of malignancy. The patient remained well until a year later when symp- toms of androgen and cortisol hypersecretion recurred. A CT scan showed a 2-cm soft-tissue mass in the tumour bed suggestive of recurrent disease. In November 2006 the patient underwent an open re-exploration with resection of the recurrent ACC and regional lymph nodes with adequate surgical margins. The histology of the resected specimens confirmed locally recurrent ACC with lymph node metastasis. She was subsequently commenced on mitotane and underwent radiotherapy to the adrenal bed. In May 2007 the symp- toms of her Cushing’s and virilizing syndrome recurred, which was confirmed on biochemistry. Repeat fluorodeoxyglucose-PET and CT suggested recurrent disease behind the pancreas, at the hilum of the spleen and in the left para-aortic region. In June 2007 the patient underwent a splenectomy, left nephrectomy, omentectomy as well as a hysterectomy and bilateral oophorectomy for disease in the pouch of Douglas discovered at the time of surgery. After surgery the patient became cortisol deficient and was commenced on predniso- lone and mitotane.
Case 2
A 39-year-old man presented with a 10-cm cortisol-secreting adrenal tumour with CT features suggestive of a malignancy (Fig. 3). He underwent an open left adrenalectomy and retroperitoneal clearance in October 2003. The pathology confirmed an ACC, which was completely excised (Fig. 4), but the closest microscopic margin was narrow with a margin of 1 mm. He was commenced on a reducing dose of prednisone and low-dose adjuvant mitotane (250 mg daily). His cushingoid features resolved postoperatively.
He remained disease free until 14 months postoperatively, until evidence of excess cortisol secretion was seen on follow-up biochemical screening. CT indicated local recurrence with lung and liver metastatic disease. He was commenced on high-dose mito- tane (8 g daily) and five cycles of chemotherapy (doxorubicin, adriamycin/cisplatin and etoposide). There was good response based on size reduction of the adrenal recurrence and distal metastases. At multi-disciplinary review an aggressive approach was decided on in
| Patient no. | Age (years)/sex | Primary surgery | Approach | Time to reoperation (years) | Site of tumour recurrence | Preoperative diagnosis | Pathology |
|---|---|---|---|---|---|---|---|
| 1 | 17/F | July 2005 | Laparoscopic | 0.4 | Incomplete resection | Residual ACC | Normal adrenal tissue |
| Nov 2005 | Open | 1 | Tumour bed | ACC | ACC | ||
| Nov 2006 | Open | 0.6 | Tumour bed and peritoneal cavity | ACC | ACC | ||
| 2 | 39/M | Oct 2003 | Open | 2.8 | Tumour bed | ACC | ACC |
| Aug 2005 | Open | 0.5 | Tumour bed | ||||
| 3 | 32/M | Oct 1999 | Laparoscopic | 3 | Residual adrenal tumour | Familial PC VHL | Recurrent PC |
| 4 | 52/M | 1996 | Open | 9 | Tumour bed | Sporadic PC | Malignant PC |
| 5 | 63/M | 1975 | Bilateral open | 29 | Organ of Zuckerkandl | Familial PC MEN2A | PC |
| 6 | 47/M | 1990 | Open | 14 | Tumour bed | Sporadic PC | Recurrent PC |
ACC, adrenocortical carcinoma; MEN, multiple endocrine neoplasia; PC, phaeochromocytoma; VHL, von Hippel Lindau.
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view of his young age and the favourable response to the chemo- therapy. A radical left nephrectomy and retroperitoneal clearance with a partial right hepatectomy (segment VIII metastatic lesions) was performed in August 2005. Histopathology confirmed meta- static adrenal carcinoma. He was recommenced on high-dose mitotane.
Six months later there was radiological evidence of recurrent metastatic disease within the left upper quadrant. (Fig. 5) In Febru-
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ary 2006 he underwent a partial left hepatectomy (segments II and III) with en bloc splenectomy and partial resection of the left hemi- diaphragm. He was discharged 6 days postoperatively with an uneventful recovery and remained fully independent on discharge.
By August 2006 there was evidence of recurrent disease in the left retroperitoneum and nodules in the para-aortic area and his pulmo- nary metastases had worsened. He died from metastatic disease in September 2006.
Case 3
A 32-year-old man with a known von Hippel Lindau (VHL) germ line mutation who presented with a 6-cm left adrenal mass under- went a laparoscopic adrenalectomy in October 1999. The pathology confirmed complete excision of the phaeochromocytoma.
Three years later he developed palpitations and flushing, similar to that of his initial presentation. Biochemical screening indicated elevated urinary catecholamines and CT imaging confirmed recur- rent disease. A 2-cm recurrent tumour in the left adrenal bed below the surgical clip applied at the initial laparoscopic adrenalectomy was found during an open left redo-adrenalectomy. Histopathology of the resected specimen confirmed recurrent phaeochromocytoma.
Case 4
A 52-year-old man was referred with metastatic phaeochromocy- toma 9 years after an open adrenalectomy for a 7 x 5 x 5-cm left
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adrenal tumour performed at another institution (Fig. 6). The initial pathology suggested a benign phaeochromocytoma. He represented with similar symptoms to his initial presentation and magnetic reso- nance imaging demonstrated a 7.5 x 6.5 × 6.5-cm mass medial to the left kidney consistent with recurrent tumour (Fig. 7). Whole-body CT and meta-iodobenzylguanidine (MIBG) scan demonstrated lung and liver metastases.
He underwent excision of the recurrent tumour in the left adrenal bed with an en bloc left nephrectomy. Histology confirmed recurrent phaeochromocytoma with clear microscopic resection margins.
Postoperatively, he underwent I131-MIBG treatment. Genetic testing for a germline mutation in RET proto-oncogene, succinate dehydrogenase subunit B and D (SDHB and SDHD) and VHL were negative. Two years after his revision surgery, despite low-volume lung and liver metastatic disease, he remains symptomatically con- trolled on long-term phenoxybenzamine.
Case 5
A 63-year-old man known to be a multiple endocrine neoplasia 2A (MEN2A) kindred underwent a bilateral adrenalectomy in 1975 at another institution. He had been on glucocorticoid, mineralocorti- coid, and androgen replacement. During surveillance, elevated cat- echolamines were detected and CT showed a 4.9-cm heterogeneous soft-tissue mass in the retroperitoneum, anterior to the lower abdominal aorta and inferior vena cava corresponding to high uptake on the MIBG scan. In July 2006 a laparotomy was performed and the tumour was resected. Histology confirmed a phaeochromocytoma in the organ of Zuckerkandl with a Phaeochromocytoma of the Adrenal Gland Sealed Score (PASS) of 6. With his hormone replacement he remains well with no evidence of recurrent disease.
Case 6
This 47-year-old man had a 10-cm left adrenal phaeochromocytoma that was surgically removed by laparotomy in 1990 in South Africa. He was symptom free until 2004, when he began developing symp- toms suggestive of recurrent disease. Biochemical tests, MIBG and abdominal CT indicated a recurrent phaeochromocytoma of 13 mm in the left adrenal fossa. There was no history suggestive of familial disease and there were no RET, SDHB, SDHD or VHL germline mutations detected with genetic testing. He had an open resection of the recurrent tumour with retroperitoneal lymph node clearance. Histology of the resected specimen confirmed a recurrent phaeo- chromocytoma. He is currently symptom free and remains bio- chemically normal.
Discussion
Prior to 1992, adrenalectomy was performed via the open method using either an anterior, lateral or posterior approach. Since then the laparoscopic anterior transperitoneal or endoscopic retroperitoneal approaches have become the standard choice for functional or large non-functional adrenal tumours because of less postoperative pain, early discharge and quicker return to normal function.4-7
Much has been documented about the indications, efficacy and outcomes for primary adrenal surgery, but little has been written about the indications, predisposing factors and outcomes of reopera- tive adrenal surgery. We have reviewed our experience from nearly 20 years of adrenal surgery, and 3.5% of the adrenalectomies were a secondary procedure, demonstrating that it is an uncommon event. There are, however, some lessons to be learnt from this experience, especially when performing the primary surgery in patients with ACC or phaeochromocytomas.
Adrenal carcinoma is a rare malignancy with an annual incidence of less than two cases per million with a poor prognosis.8-10 Despite novel techniques in the management of these tumours, surgery is still the mainstay of treatment. Recurrence rates after apparent complete resection surgery have been reported to be from 35% to 85% in various series.9,11 Although the prognosis of ACC is still poor, surgery is still the only effective treatment for primary and recurrent disease.9,10,11
Schulick and Brennan had reported a recurrence rate after primary resection for ACC to be 44% with 83 repeat resections in 47 patients with one patient having seven re-resections.11 The most important factor leading to local recurrence was the completeness of resection. In the present series complete resection was achieved in both cases of ACC, but recurrences still occurred within 1 and 2.8 years for patients 1 and 2, respectively. Gröndal et al. compared the survival in patients who underwent a second surgical procedure versus those who received chemotherapy after recurrence and showed a longer survival in the surgical group.12 Greater median survival has been reported in patients who were treated aggressively with surgical excision for tumour recurrences versus those treated medically (56 vs 19 months).13,14 Several combinations of cytotoxic agents have been used, and the available evidence suggests that cisplatin alone or in combination with etoposide has some activity in ACC. Only a minority of patients, however, respond to current protocols, with the exception of a treatment regimen from Italy combining mitotane with etoposide, doxorubicin, and cisplatin.15
Mitotane (o,p’-DDD) is the only adrenal-specific agent available for treatment of ACC. Mitotane exerts a specific cytotoxic effect on adrenocortical cells, producing focal degeneration of the fascicular and particularly the reticular zone, whereas changes of the zona glomerulosa are relatively slight. The benefits of adjuvant mitotane therapy for localized disease haves been controversial, and thus for patient 1 was not administered postoperatively. Recent work by Terzolo et al. published subsequent to the index surgery suggests that adjuvant mitotane may prolong recurrence-free survival after resection of localized ACC.16 Patient 2 responded favourably to the combination of cytotoxic chemotherapy and mitotane, which led to the decision of debulking surgery. Radiotherapy has been previously considered ineffective for treatment of ACC although some reports have described tumour response rates up to 40% for radiotherapy.17 Fassnacht et al. suggest that adjuvant tumour bed irradiation is effec- tive in reducing the high rate of local recurrences in ACC, but this does not confer a survival benefit because there is no alteration in the development of distant metastatic disease.18 In the light of this new literature, patients 1 and 2 might have benefited from adjuvant radio- therapy to the tumour bed after the initial excision, because this may have reduced the likelihood of reoperation for recurrent localized disease. Patient 1 had further surgery after adjuvant radiotherapy to the left adrenal bed and retro-peritoneal region. The radiotherapy did not appear to affect tissue planes or cause greater fibrosis than one would expect from her previous surgical procedures.
The role of debulking surgery during the latter stages of disease is controversial, with some groups suggesting benefit11 while others suggest that surgical palliation does not add to survival benefit.19 Patient 2 had debulking surgery to palliate his hyperfunctioning state, because he was young and his disease was stable. Debulking
surgery is done to reduce tumour volumes in patients who have functional metastatic disease. This may offer effective palliation of a hyperfunctioning state, which can be difficult to control medically, as seen in patient 1.
Surgical technique and appreciation of the anatomy is important to ensure complete resection of the adrenal gland. The adrenal glands are retroperitoneal organs resting on the crura of the dia- phragm on either side of the vertebral column (T11-12), against the supero-medial surface of the corresponding kidney, surrounded by a thin fibrous capsule. The right adrenal gland is pyramidal in the apex with its medial and lateral limbs embracing the kidney. Occasionally the medial limb may be wedged behind the inferior vena cava. The left adrenal gland is crescentic and semilunar in shape and extends further inferiorly on the medial margin of the kidney.20 Effort must be made to resect all of the adrenal gland as a subtotal resection will increase the risk of recurrent disease. The macroscopic appearance of the adrenal gland can be unreliable when used to identify the gland intraoperatively, because the appearance may be similar to surrounding perirenal fat, particularly to the inexperienced surgeon. It generally has a slightly darker yellow colour and has a finely granular surface and firm consistency compared to the surrounding perirenal fat. It is because of this unclear distinction from the sur- rounding fat that some have advocated resection of the adrenal gland with a generous cuff of Gerota’s fascia.
In two of the present cases of recurrent phaeochromocytoma, recurrence occurred due to adrenomedullary tissue left behind at the primary operation. In patient 3, at open reoperation, tumour had clearly recurred beneath the clip placed at the laparoscopic adrena- lectomy 3 years prior, in a tongue of tissue below the renal vein. Similarly, local recurrence below the renal vein occurred in medulla left behind at the primary operation in patient 6. We postulate that the large local malignant tumour in patient 4 may have risen from incomplete resection. It is now recognized that 11.6% of apparently sporadic phaeochromocytomas carry an SDHB or SDHD germline mutation,21 and that 37.5% of SDHB-positive phaeochromocytomas are malignant.22 Therefore complete resection of all ipsilateral adrenomedullary tissue should be the goal of surgery for all adrenal phaeochromocytoma.
Patients with hereditary phaeochromocytoma often develop mul- tiple or bilateral adrenal tumours at a young age and are prone to recurrences. The mode of management for these tumours is contro- versial, some performing a cortical-sparing adrenalectomy, while others, a total adrenalectomy. The latter may be attractive to some surgeons because they avoid reoperation if the tumour recurs. To avoid lifelong dependence on steroid replacement from a bilateral adrenalectomy, adrenal-sparing surgery, which maintains adrenocor- tical function, can be considered for patients with MEN2 and VHL and SDHD germline mutations because the risk of malignancy is low (<5%). The major drawback of partial adrenalectomy is the risk of recurrent tumours in the adrenal remnant because some medullary tissue is inevitably left behind within the spared cortex. Such ‘recur- rence’ can be a formation of a new tumour due to genetic predispo- sition or recurrence from incomplete resection of the original tumour. Neumann et al. reported one patient with VHL disease with ipsilateral recurrence out of 29 patients undergoing partial adrena- lectomy.23 Walther et al. reported a recurrence in 1 of 13 patients
during a median follow up of 18 months.24 Nambirajan et al. reported the Austrian experience of laparoscopic partial adrenalec- tomy in five patients with hereditary phaeochromocytoma (four with VHL disease and one with MEN2B), who had undergone adrenal surgery previously, and who presented with recurrent adrenal tumours.25 They have also concluded that because they do expect recurrences to occur, a minimal invasive approach is ideal. Hence, it is essential to weigh the benefit of preserving adrenal function against the risk of recurrent tumours.
Follow up is essential for patients who had adrenalectomies. Those who had surgery for adrenal carcinomas need close follow up due to the propensity of recurrence, either in the tumour bed or metastatic spread. Patients with hereditary phaeochromocytomas, as illustrated in cases 3 and 5, presented 3 and 29 years later, respec- tively, thus mandating close follow up due to the natural history of recurrence of the disease. In the present study the two patients with sporadic phaeochromocytomas (cases 4 and 6), who had curative surgery, presented with recurrences at 9 years and 14 years after index surgery, respectively. This supports the premise that there should be lifelong follow up for all patients treated with phaeochro- mocytoma. With functioning tumours, hormonal markers can be measured for early detection of recurrence, but in most patients imaging is more sensitive for monitoring tumour recurrence. The recommended length of follow up for patients after surgery is con- troversial. Our recommendation is lifelong follow up for all patients who have had excision of a functional adrenal tumour and for all patients with an adrenal incidentaloma that is malignant or of uncer- tain malignant potential (as per the Weiss histological criteria).
The approach of reoperation will depend on the pathology and the experience of the surgeon. As with the index procedure, the aim is for the successful excision of the recurrent disease with low postop- erative morbidity and mortality. Malignant phaeochromocytomas and ACC most commonly disseminate haematogenously, but they may also metastasize via the lymphatic system. An oncological resection for malignant adrenal disease should therefore include complete excision of retroperitoneal fat and fascia as well as regional lymph nodes. Nephrectomy should be performed if there is invasion of the kidney or renal vessels. Although there is no evidence that this approach improves overall survival it may reduce the inci- dence of local recurrence. In the nine cases of reoperative adrenal surgery we report, the surgeons chose an open approach with the key objective to achieve good clearance and remove any possible remnant tissue left in the tumour bed, which could lead to further recurrence. There were no documented postoperative complications and no mortality, which is similar to other published series of reop- erative surgery.11,26
Conclusion
Reoperative adrenal surgery is an uncommon event and accounted for 3.5% of all adrenalectomies in the University of Sydney Endo- crine Surgical Database over a 20-year period. During the index surgery for adrenal tumours, effort must be made to remove all of the ipsilateral adrenal gland and associated adrenal tissue, especially when operating for ACC and phaeochromocytoma, for which the
risk of recurrence is high. If tumour recurrence occurs, then imaging to exclude metastatic disease is essential and a thoughtful decision made as to the benefits of local reoperative surgery. Reoperative adrenal surgery is a safe procedure and may confer survival benefit or symptom relief. All patients who have had surgery for functional, malignant or non-functioning adrenal tumours of uncertain malig- nant potential should have lifelong follow up.
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