P. Langer D. Bartsch E. Moebius M. Rothmund C. Nies
Adrenocortical carcinoma - our experience with 11 cases
Received: 1 December 1999 Received in revised version: 28 April 2000 Accepted: 8 May 2000 Published online: 7 October 2000 @ Springer-Verlag 2000
P. Langer () . D. Bartsch . E. Moebius M. Rothmund · C. Nies Department of General Surgery, Philipps-University Marburg,
Baldingerstrasse, 35043 Marburg, Germany e-mail: langerp@post.med.uni-marburg.de Tel .: +49-6421-2866441 Fax: +49-6421-2868995
Abstract Background and aims: Adrenocortical carcinoma (ACC) is a rare tumour with an incidence of approximately 0.5-2 cases per mil- lion per year. Diagnosis is mostly delayed and prognosis is poor. We report our experiences with 11 pa- tients operated on within the last 10 years. Patients/Methods: The da- ta of the patients with ACC were re- viewed and presenting symptoms, diagnostic procedures, treatment and results of follow-up were evaluated. Results: The group of patients con- sisted of eight women and three men with a mean age of 40.2 (15-57) years. Median follow-up was 16 (1-71) months. Six patients present- ed with Cushing’s syndrome, two presented with virilism and hirsut- ism caused by androgen-producing tumours. Three patients had hor- monally inactive tumours. At the time of diagnosis, five tumours were classified as stage II, two as stage III and four as stage IV. Four patients had tumours with intravascular ex- tension, prompting recurrence in two cases. Eight adrenalectomies, one resection of local recurrence,
one adrenalectomy with splenecto- my and one adrenalectomy and re- section of a liver metastasis were performed. Five patients received additional chemotherapy. Five of the 11 patients are still alive (three stage II, one stage III and one stage IV at the time of diagnosis), three of whom have no evidence of disease (14, 48 and 71 months after sur- gery). The other six patients died af- ter a median postoperative period of 10 (1-21) months. Conclusions: Ve- nography should be performed prior to surgery to detect or exclude thrombotic tumour masses in the su- prarenal vein, renal vein or inferior vena cava. Radical surgery is the on- ly curative approach and is recom- mended for all patients with resect- able tumours, including those pa- tients with recurrent disease. There is no consensus concerning adjuvant therapy. The value of multidisciplin- ary strategies needs to be assessed in multicentre trials.
Key words Adrenocortical
carcinoma · Vena cava involvement · Mitotane · Results of surgery
Introduction
Adrenocortical carcinomas (ACC) are rare malignancies with an incidence of approximately 0.5-2 per million per year. Because of its very low incidence, experiences of single institutions with this tumour are limited. Only a small number of specialized centres have been able to
publish larger series [1, 2, 3, 4, 5]. The first series was published by Rapaport et al. [6] in 1952. Since then, sev- eral reports have been published with different conclu- sions regarding the epidemiology and appropriate treat- ment of these tumours. A major disadvantage of the larg- er series from single institutions is the fact that patients were collected over very long time periods with chang-
| T1 | Tumour <5 cm |
| T2 | Tumour >5 cm |
| T3 | Tumour infiltrates perirenal fatty tissue |
| T4 | Tumour infiltrates neighbouring organs |
| Na | No evidence of lymph node metastases |
| Nb | Mobile lymph node metastases |
| N. | Fixed lymph node metastases |
| M | Distant metastases |
| Stage I | T1, Na |
| Stage II | T2, Na |
| Stage III | T3, Na; T1, N}; T2, Nb |
| Stage IV | T4, No or M in any combination |
ing therapeutic strategies, operative techniques and pos- sibly different drugs for adjuvant medical treatment. This makes a meaningful comparison of the data difficult.
The mainstay of any treatment regimen is the com- plete surgical removal of the tumour.
Unresponsiveness of the tumour to chemotherapeutic agents adds to the poor overall survival rate. The value of adjuvant therapy is, therefore, still a matter of contro- versy, although the introduction of o,p’DDD (mitotane) was greeted with some enthusiasm [7]. In this study we retrospectively reviewed the data of 11 patients operated on for ACC between 1989 and 1999. The clinical presen- tation, treatment and outcome of these patients are pre- sented and compared with data from the literature.
Material and methods
Clinical data of all patients with ACC treated at the Department of General Surgery of Philipps-University, Marburg, Germany, be- tween 1989 and 1999 were retrospectively reviewed. Since 1993, the data of all patients with adrenal tumours have been prospec- tively documented. Data of patients operated on prior to 1993 were obtained by chart review. The tumours were staged accord- ing to Macfarlane’s [8] classification (Table 1). The follow-up data of four patients were obtained by personal examination in the out- patient clinic. In the remaining seven cases, the general practitio- ners of the patients were contacted to obtain follow-up data.
Results
Patients characteristics and clinical presentation
Eleven patients (eight women and three men) were oper- ated on for ACC between 1989 and 1999. Mean age at the time of diagnosis was 40.2 (15-57) years. Six pa- tients presented with Cushing’s syndrome, while hirsut- ism and virilism were clinically obvious and prompted further investigation in two patients. Three patients had hormonally inactive tumours. One of these patients pre- sented with abdominal pain. The other two patients were asymptomatic and tumours were found during routine in-
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vestigations; a palpable abdominal mass was present in one of them. One patient initially presenting with Cush- ing’s syndrome and a stage II tumour was referred from an outside hospital with locally recurrent disease and distant metastases 2 years after initial adrenalectomy. At the time of diagnosis, five tumours were classified as stage II, two as stage III and four as stage IV.
Primary treatment
All patients underwent surgery. Adrenalectomy includ- ing regional lymphadenectomy was performed in eight cases, while resection of local recurrence including ne- phrectomy and resection of a liver metastasis was per- formed in one case. Adrenalectomy with resection of a single liver metastasis was performed as the primary pro-
| Patient | Stage | Operation | Tumour size (cm) | Outcome | Survival time (months) |
|---|---|---|---|---|---|
| 1 | II | AE+LA | 20×14×12 | NED | 48 |
| 2 | II | AE + LA | 12×7.5×7 | DOD | 21 |
| 3 | IV | AE+nephrectomy+resection of liver-met. | Unknown | DOD | 1 |
| 4 | III | AE + LA | 9.5×8.5×6.5 | DOD | 16 |
| 5 | II | AE + LA | 8×8 | NED | 71 |
| 6 | IV | AE + LA | 20×15×18 | AWM | 16 |
| 7 | II | AE + LA | 11×12×12 | AWM | 24 |
| 8 | IV | RLR + nephrectomy + resection of liver metastases | 8.5 diameter | DOD | 4 |
| 9 | II | AE+LA | 9×9×12 | DFDR | 14 |
| 10 | IV | AE+LA+tumour thrombectomy | 10.5×7×8 | DOD | 6 |
| 11 | III | AE+LA+tumourthrombectomy | 17×10×8 | NED | 14 |
cedure in another patient. Adrenalectomy and splenecto- my were also performed in one case.
Tumour thrombi were removed from the renal vein in one case and from the right suparenal vein in another (Figs. 1 and 2). At the time of diagnosis, tumour size ranged from 8 to 20 cm.
One patient died 36 days after adrenalectomy and re- section of a liver metastasis from haemorrhagic shock as a result of postoperative bleeding. Another patient re- quired successful re-operation for postoperative haemor- rhage. Necrosis of the kidney necessitated re-operation and left nephrectomy in a patient in whom a branch of the renal artery was encased by the tumour requiring transection during the initial procedure. This patient also had a tumour thrombus removed from the renal vein.
Adjuvant therapy
Seven patients received adjuvant or palliative chemo- therapy. Only two of them were treated with mitotane alone. The other five patients received different agents under different protocols, including cisplatin and adria- mycin.
Outcome
Two patients developed thrombotic masses in the vena cava as local recurrences. The mass was resected in one case in an outside hospital. No tumour was suspected in the venous system at the time of initial surgery in either patient. However, it is most likely that the recurrences developed from residual tumour tissue not removed dur- ing the primary operation. The recurrences occurred 5 months (G3 tumour) and 10 months (G1 tumour) after initial surgery. One patient initially not thought to have metastatic disease developed pulmonary metastases 8 months after surgery. Four of the 11 patients died dur-
ing follow-up as a result of progressive tumour disease, one owing to surgical complications. The median post- operative survival of this group was 6 (1-21) months. One patient with stage II disease at presentation died fol- lowing an accident and subsequent mycotic pneumonia 14 months after adrenalectomy. At that time there was no evidence of recurrent disease. Five patients are still alive, two of whom currently received chemotherapy for metastases 16 and 24 months after surgery. The remain- ing three patients are free of disease 14, 48 and 71 months after surgery (Table 2).
Discussion
ACC is a rare malignancy with a dismal prognosis. Al- though some larger series of patients with this challeng- ing disease have been published in the last decade [4, 9, 10, 11, 12], survival rates remain poor and effective ther- apeutic alternatives to surgery are still being sought.
The clinical characteristics of our patients are similar to those of the patients reported in the literature [9, 13, 14, 15, 16]. Similar to previous studies, we found that ACC affected females more commonly. Hyperfunction- ing tumours were more frequent than hormonally inactive ones. The most common clinical presentation was Cush- ing’s syndrome followed by virilization in female pa- tients. Patients with hormonally inactive tumours mostly felt abdominal discomfort or pain as a result of signifi- cant tumour size. Symptoms such as fever, weight loss or weakness were not encountered in our patients. These symptoms have been reported to be poor prognostic signs [10]. Other patient characteristics (age, sex, hormonal ac- tivity) have not been shown to be of prognostic value.
Unfortunately, most patients are seen in advanced stages of the disease, which sometimes makes complete resection difficult or impossible [3, 9, 13, 17]. More than half of our patients presented with stage III and IV tu- mours. All lesions had already reached a considerable
size. Similar observations have previously been reported [2, 3, 5, 9, 16, 17, 18, 19]. Tumour stage at the time of diagnosis has been cited in the literature as the most im- portant prognostic factor [14, 20]. Icard et al. [13] re- ported the results of a French multicentre trial with me- dian survival times for stage I, II, III and IV tumours of 34, 40, 22 and 8 months, respectively. In our limited se- ries, two out of five patients with initial stage II disease are alive with no evidence of disease. Small ACCs (stage I) are rarely diagnosed for several reasons. ACCs are rapidly growing tumours and the time window to diag- nose and treat a small tumour is small. Furthermore, the histological diagnosis of a small malignant adrenal tu- mour is difficult and small tumours may therefore be misdiagnosed as benign [21].
In addition to the patient who was referred to us while already suffering from recurrent disease, two patients in our series developed local recurrences. In both cases, thrombotic tumour masses in the vena cava, probably originating from residual tumour tissue in the suprarenal vein or inferior vena cava, were found. Both tumours orig- inated from the right adrenal. In two additional patients, tumour tissue was intraoperatively found in the venous system, involving the suprarenal vein in a patient with a right adrenal tumour and the left renal vein in a patient with a left adrenal carcinoma. In both cases, the tumour as well as the tumour thrombus were completely resected. One patient is still free of disease;the other had presented initially with distant metastases and died 6 after surgery.
Involvement of the inferior vena cava in patients with ACC was first described by Castleman et al. [22]. It is hypothesized that this is true for approximately 30% of patients with ACC [23, 24]. Right-sided tumours are es- pecially prone to venous involvement [21, 25, 26]. Hedi- can and Marshall [24] reviewed 26 patients with vena cava tumour involvement described in the literature be- tween 1972 and 1997. In 82.8% of these patients, the pri- mary tumour affected the right adrenal gland [24]. Tu- mour thrombi can be of significant size, sometimes reaching the right atrium, and thus can make complete resection difficult and dangerous, if the situation is not known prior to surgery. Hedican and Marshall [24] found 58% of the intracaval thrombi attaining a supradiaphrag- matic level. Cardiopulmonary bypass may be necessary to reduce the risk of lethal thromboembolism during re- section of these tumours [27, 28]. For this reason, mag- netic resonance imaging (MRI) or conventional veno- gram have been recommended prior to surgery in pa- tients with right-sided ACCs larger than 9 cm [24]. Our data support this recommendation because four out of 11 patients had evidence of tumour tissue extending into the venous system. It is debatable whether imaging of the re- nal veins and the inferior vena cava should also be per- formed in patients with small ACCs. No data are avail- able regarding this issue. However, this question con- cerns only a very small number of patients because in
most cases ACC is diagnosed only in advanced stages with considerable tumour sizes. In addition, it is difficult to make a preoperative diagnosis of ACC in patients with small tumours. Imaging of the venous system was not performed routinely in our institution prior to this study, but it is now. Compared with conventional venog- raphy, MR phlebography has several advantages. Above all, it is a non-invasive procedure. Furthermore, the sur- rounding abdominal tissues and organs can be visualized by MRI in the axial, sagittal and coronal planes, allow- ing an exact evaluation of tumour extension with special regard to the diaphragm and hepatic vasculature to plan an appropriate surgical approach [26]. In addition, the re- nal veins are difficult to image in conventional venogra- phy, which is an important drawback especially in pa- tients with left-sided tumours. The impact of intravenous tumour extension on survival rates is unknown. Libertino et al. [29] reported a 5-year survival rate of 70% in pa- tients with renal carcinoma and involvement of the infe- rior vena cava. However this is a different tumour entity, which has an overall much better prognosis than ACC.
The mainstay of therapy for ACC is radical surgery whenever possible [30]. Pommier and Brennan [3] re- ported a 5-year survival rate of 47% for patients who un- derwent complete resection of the tumour. The authors also recommended surgery as the treatment of choice for recurrent or metastatic disease whenever complete resec- tion is possible. Patients with long disease-free intervals particularly benefit from repeat surgery [20].
The role of chemotherapy is still a matter of debate. High response rates to mitotane treatment were reported in the late 1960s and early 1970s; however, no effect on survival was observed [7, 31]. More recent studies are also not very encouraging. Partial response rates of 19-34% with no impact on survival have been reported by several authors [2, 3, 5, 20, 32], while others demon- strated improved survival in patients whose tumours re- sponded to mitotane [33]. Furthermore, significant side effects are associated with this treatment. Nausea, vomit- ing and diarrhoea, as well as depression, are the most frequently reported problems[34]. In addition, the toxic effect on the unaffected adrenal gland may make lifelong steroid replacement therapy necessary. To date, no pro- spective, randomized controlled trial has been published concerning the efficacy of mitotane and there seems to be no consensus regarding adjuvant or palliative medical therapy. Medical treatment with mitotane alone in cases of unresectable disease has been recommended to con- trol hormonal excess, if evident, and to try to decrease the rate of tumour progression [3, 19]. Blood levels of the drug have to be controlled carefully and therapy should be discontinued if no response is documented.
Other agents used in the treatment of ACC include cisplatin, suramin, adriamycin and a-interferon. None of them has been shown to be of significant benefit. Six of our 11 patients received chemotherapy. Two of them
were treated with mitotane alone; the others received combinations of different drugs. However, there is no de- fined protocol for the adjuvant or palliative treatment of patients with ACC in our institution. This again shows the therapeutic confusion owing to the lack of sufficient data. Because ACC is so rare, multicentre trials are need- ed to evaluate new protocols.
The only justification for radiotherapy is palliative treatment of bone metastases for pain relief [18,35].
Conclusions
Radical surgery is the only curative approach to patients with ACC. Venography of the vena cava is recommend- ed as a routine diagnostic tool, at least in patients with large tumours, to demonstrate or exclude tumour exten- sion into the venous system. There is still no consensus on adjuvant therapy and multicentre trials are needed to assess the value of multimodal therapeutic strategies.
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