ELSEVIER
SCIENCE
d DIRECTO
EJSO the Journal of Cancer Surgery
Experience with the surgical treatment of adrenal cortical carcinoma
A. Meyerª, U. Niemannb, M. Behrend“,*
ªAbt. Strahlentherapie, Med. Hochschule, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany bAbt. Viszeral- und Thoraxchirurgie, Klinikum Detmold, Röntgenstr. 18, 32756 Detmold, Germany “Klinik für Viszeral-, Thorax-, Gefäß- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Str. 41, 94469 Deggendorf, Germany
Accepted for publication 29 January 2004
KEYWORDS
Adrenal tumour; Adrenal carcinoma; Outcome; Surgery
Summary We report on a series of 20 consecutive patients (10 males, 10 females) with adrenal cortical carcinoma (ACC) who were treated by surgery between 1987 and 2001.
Aim. The aim of this study was to evaluate the outcome and the role of surgery in the management of this tumour.
Result. One patient was at stage I, five patients at stage II, five patients at stage III and nine patients at stage IV of disease. Ten patients suffered from a functioning tumour, whilst ten patients revealed non-functioning tumours. In all patients a transabdominal approach was performed for the complete resection of the tumour, adjacent organs or metastases. The medium survival after surgical resection, calculated by the Kaplan-Meier method, was 45 months for the overall group, 65 months for patients at stage I or II, 38 months for patients at stage III and 19 months for patients at stage IV of disease. The 5-year survival rate for all patients was 23%, for patients at stage I or II 33%, for patients at stage III 20%, and for patients at stage IV around zero.
Conclusion. Radical surgery with a complete resection of the tumour, adjacent organs, solitary metastases and loco-regional recurrence wherever possible improves survival, even at advanced stages of disease.
@ 2004 Elsevier Ltd. All rights reserved.
Introduction
Adrenal cortical carcinoma (ACC) is a rare and highly malignant tumour with a world-wide annual incidence of approximately 0.5-2 cases per million and accounts for 0.2% of all cancer-related deaths.1,2 This low incidence contrasts strongly with the high and increasing incidence of benign adrenal lesions and incidentalomas. 3,4 With respect
to the ability, quantity and quality of hormone production, ACC can be divided in functioning and non-functioning tumours. Due to the very low incidence and the infrequent occurrence reports on greater series of this tumour are rare.5-16 One of the major disadvantages of most series is the recruitment of patients over a longer period of time with changing therapeutic strategies. Because of the rarity of this tumour and the location of the adrenal glands, which are inaccessible for clinical examination, the diagnosis is often delayed. There- fore, most patients present at advanced stages of disease. The tumour’s unresponsiveness to
chemotherapeutic agents additionally worsens the poor prognosis.
The mainstay of therapy is still the radical surgical resection of the tumour and adjacent organs. The increased risk of ACC was associated with cigarette smoking amongst men and the use of oral contraceptives amongst women.17 ACC is also related to the Li-Fraumeni-syndrome and the Beck- with- Wiedemann syndrome. 4,17,18 In this study, we reviewed the data of all patients operated on ACC between 1987 and 2001 in our institution.
Patients and methods
The clinical charts of 20 patients (10 males, 10 females) who underwent adrenalectomy for ACC at our institution between 1987 and 2001 were reviewed. Demographic data, clinical history, pre- operative laboratory and imaging studies, surgical treatment, pathological findings and the post- operative course were reviewed. We evaluated the symptoms of the patients, the period between the first symptoms and diagnosis, the staging, the sites of metastases, the surgical procedures, the morbidity and the long-term survival. All patients underwent clinical, radiological and hormonal evaluation. The steroid serum hormones evaluated were glucocorticoids, mineralocorticoids, andro- gens, estrogens and precursors of these hormones. The endocrine evaluation included the simul- taneous measurement of plasma cortisol and plasma ACTH at baseline conditions and in combi- nation with the dexamethasone suppression test, the simultaneous measurement of plasma aldoster- one and plasma-renin-activity, the measurement of 24-h urinary free cortisol and 24-h urinary aldosterone, the measurement of hydroxypro- gesterone, testosterone, androstendione and estradiol.
The tumours were classified as functioning or non-functioning, depending upon whether the patients revealed endocrine symptoms or not. Functioning tumours are defined as showing signs and symptoms of adrenal hormone production. Non- functioning tumours are defined as seen in any other manner, even if subtle production of hor- mones or precursors is subsequently revealed by laboratory analysis.
The pre-operative evaluation of malignancy was carried out with radiological methods including sonography, computed tomography (CT), magnet resonance imaging (MRI), angiography and imaging- guided fine-needle aspiration. The CT character- istics taken into account were irregular shape and
margins, lobulation, lack of heterogenity, haemor- rhage, central necrosis and the invasion of adjacent organs. The MRI characteristics used were the lack of fat suppression, heterogeneous signal intensity on T1- and T2-weighted images and the existence of tumour thrombus, particularly in the inferior caval vein.
Post-operatively, the diagnosis of malignancy was confirmed by histologic examination in all patients. The histological parameters used by the system proposed by Weiss were size, high nuclear grade, high mitotic rate, atypical mitotic figures, eosinophilic tumour cell cytoplasm, diffuse archi- tecture, necrosis, invasion of venous structures, invasion of sinusoidal structures and capsular invasion. 19
Staging of the patients was performed on the basis of radiological examination, operative find- ings, pathologic specimens and the presence of metastases according to Macfarlane’s classification modified by Sullivan et al. Patients with stages I and II of disease revealed tumours confined to the adrenal gland without local invasion or distant metastases. The largest tumour dimension was <5 cm at stage I or > 5 cm at stage II. Evidence of lymph nodes metastases or local tumour invasion without involving adjacent organs was defined as stage III. Invasion of adjacent organs or the presence of distant metastases was defined as stage IV of disease. The goal of each surgical approach was the complete excision of the primary tumour and any adjacent organs and tissues.
Follow-up of the patients was carried out by regular re-examination in our endocrine outpatient clinic or by personal contact with the patient’s primary physician. The mean post-operative survi- val period was calculated by the method of Kaplan- Meier.
Results
Patients and symptoms
In 19 of the 20 patients, the diagnosis of ACC was suspected pre-operatively, in one patient the presence of ACC was recognized intraoperatively. Ten patients suffered from functioning tumours, whilst 10 patients revealed non-functioning tumours. The group of patients with a functioning tumour consisted of seven women and three men, the group of patients with a non-functioning tumour consisted of three women and seven men. The mean age of the patients at the time of the operation was 49.5 years (males 59.0, females
39.9). The mean age of patients with a functioning tumour was 46.9 years in comparison to 52.1 years for patients with a non-functioning tumour.
Stage of disease
One patient was at stage I, five patients at stage II, five patients at stage III and nine patients at stage IV of disease. No difference was noted between the staging between patients with a functioning and those with a non-functioning tumour (Table 1). In the group of patients with functioning tumours virilization was seen in two patients. The stigmata of Cushing syndrome including an increase in weight with truncal obesity, rounded face, buffalo hump and glucose intolerance was seen in three patients. A combination of both virilization and of Cushing syndrome was seen in five patients. In all patients the hormone excess was proven by endocrine evaluation. Amongst patients with a non-function- ing tumour, six patients suffered from unspecific symptoms such as abdominal pain or discomfort. A further four patients were asymptomatic and the tumour was discovered incidentally during a routine sonography of the abdomen. Of these four patients one was at stage I, two at stage II and one at stage IV. The mean interval between initial symptoms and diagnosis was 7 months with no difference between functioning and non-functioning tumours.
Diagnostics
A sonography of the abdomen was performed on 17 of 19 patients, a CT on 18, a MRI on nine, an angiography on eight and an urography on three patients. Fine-needle cytology of the adrenal lesion was performed on five patients pre-operatively. The result was PAP V in four patients and PAP II in one patient. Metastases were discovered pre- operatively in eight patients with the liver, the lymph nodes and the liver and lung involved in each two patients and the lung and the lung and bones in each one patient.
Surgery, complications and histology
A transabdominal approach was used on all patients
with a mean operating time of 197 min. The operation was commenced on one patient via a dorsal retroperitoneal approach, but because of the intraoperative suspicion of malignancy the oper- ation was converted to a transabdominal approach. Local invasiveness leads to additional resections including a hemihepatectomy (1), cholecystectomy (2), nephrectomy (4), partial resection of the caval vein (4), renal vessels (2), phrene (1), and sple- nectomy (2). Because of metastases, a hemihepa- tectomy was performed on two patients and a lobectomy via a transabdominal approach with a phrenotomy and a Wedge-resection on one patient. Intraoperative complications occurred in four patients including bleeding from the liver, injury to the inferior caval vein and opening of the tumour intraoperatively in each one patient. Post-opera- tively, 18 of 20 patients (90%) were submitted to the intensive care unit for a mean stay of 34 h. Post- operative complications arose in six patients including pneumonia with cutaneous mycosis, pre- viously unknown bone metastases, wound dehis- cence, wound infection and pulmonary embolism in each one patient. One patient died due to post- operative complications. This patient suffered from lung-embolism with global respiratory insufficiency making intubation necessary on the second post- operative day. Death occurred on the 56th day due to bronchopneumonia and renal failure. The post- operative pathological examination confirmed the diagnosis of ACC in all patients. The mean diameter of the tumour was 13.3 cm with a mean weight of 897.1 g. The tumour was located on the right side in 14 patients and on the left side in six patients.
Follow-up
Nineteen patients were discharged from hospital. Seven of these 19 patients attended the follow-up programme. Thirteen of the 17 patients died after a mean post-operative period of 1.6 years after the initial operation. Four patients are still alive. From these four patients, two were classified as stage II, one at stage III and one at stage IV. The two patients classified as stage II, 8.5 and 11.2 years after the operation are free of disease. In the patient at stage III several local recurrences were discovered, which
| Staging | All patients (n) | Patients with functioning tumour (n) | Patients with non-functioning tumour (n) |
|---|---|---|---|
| Stage I | 1 | 0 | 1 |
| Stage II | 5 | 2 | 3 |
| Stage III | 5 | 3 | 2 |
| Stage IV | 9 | 5 | 4 |
were treated by re-operation. 10.6 years after the initial operation no sign of local recurrence or distant metastases was found. In one patient at stage IV, 4.0 years after the initial operation with lobectomy due to the existence of a solitary lung metastases, local recurrence and metastases in the lung and liver were noted. The mean post-operative survival for all patients, calculated by the method of Kaplan-Meier, is 45 months (Fig. 1). When patients with stage I and II are grouped together, the mean survival is 65 months in comparison to the patients at stage III with 38 months and at stage IV with 19 months (Fig. 2). The 5-year survival rate for all patients is 23%. For patients at stage I or II 33%, for patients at stage III 20%, and for patients at stage IV around zero.
Discussion
Presentation
Hormone excess in combination with ACC is found in about 40-70%.4,5,7,8,10- 12,14,16,18,20-23 The predomi- nance of functional tumours in surgical patients can be explained by the easier detection at an earlier stage of disease. The major symptoms of function- ing tumours are virilization in women, the classical stigmata of Cushing syndrome in both sexes or a mixture of both virilization and Cushing syn- drome. 3-5,7-12,16,18,20,23 Functioning tumours reveal- ing pure hyperaldosteronism are rare.3,4,8,11,12,20,23 The clinical picture of functioning tumours can vary due to the changing quality or quantity of hormone production.12,15 In comparison to benign
100
80
Survival in %
60
40
20
0
0
20
40
60
80
100
120
140
Time since surgery in months
100
Stage I and II
Stage III
80
Stage IV
Survival in %
60
40
20
0
0
20
40
60
80
100
120
140
Time since surgery in months
hormonesecreting lesions of the adrenal gland functioning, ACC’s show a more massive hormone excess and production of hormone precursors. Non- functioning ACC’s can be seen in 30-60% of the patients.5,11,12,14,20-23 In our series both were equally distributed. Non-functioning ACC can also produce steroid hormones or precursors of hor- mones in low doses, which are unable to cause clinical symptoms. Thus, an accurate pre-operative biochemical determination should be carried out in symptomatic and asymptomatic patients in order to avoid post-operative adrenal insufficiency.3,23 Unspecific abdominal discomfort or pain as a result of rapid growth, significant tumour size or local invasion are the major symptom in patients with non-functioning tumours. 3,5,9,11,12,18,23 Patients with ACC reveal a bimodal age distribution with an increased incidence in the first, the forth and fifth decades. 3,5,7 - 13,15,16,18,21 -23,25 Non-functioning tumours were more common in males and at a more advanced age, whereas functioning tumours occur frequently in women at an earlier age.7,10-12,21
The primary method of radiological examination in patients with the suspicion of a malign adrenal lesion is sonography. Most ACC’s can easily be detected because of the large size of the adrenal lesion. For pre-operative staging a CT is common practice.3,15,23 The further differentiation of the dignity and for visualising the tumour on different planes an MRI can be useful. MRI can distinguish between ACC and benign adrenal adenoma on the basis of signal intensity of the lesion on T1- and T2- weighted images.3,15,23 With the use of all these non-invasive imaging procedures a fine-needle aspiration is reserved for still unclear cases.
With the use of MRI an infiltration or a tumour thrombus in the renal vein or the inferior vena cava can be revealed or excluded more easily in comparison to angiography.3,15,23 An infiltration or a thrombus in the caval vein should be excluded pre-operatively. The thrombus can be of a signifi- cant size reaching up to the right atrium, rendering a complete resection difficult,27 however, it is no contraindication. The various levels of caval involvement can greatly influence the surgical approach and the extent of the operation. 3,27
Treatment
Because of unspecific signs and the inaccessibility for a clinical examination of the adrenal glands, up to 70% of the patients present at an advanced clinical stage of Ill or IV.5,7-14,20-23,28 At the time of diagnosis metastases had developed in 40% of our patients with the lung and liver being the most frequent sites. However, the only curative thera- peutic option is the complete resection of tumour and metastases, whenever possible. This aggressive surgical approach was used in all our patients. The surgeon should be prepared for the en bloc resection of adjacent organs including the kidney, liver, spleen, pancreas and inferior caval vein. A routine resection of the kidney produced no improved survival prospects.3,8,11,13 Today, it is generally accepted that whenever malignant lesions are expected, an endoscopic approach is contraindicated.4 The prognosis for untreated patients is very poor with a mean survival of only 3-6 months. Patients with an incomplete resection have a mean survival of about one year with a 5- year survival rate of 0-9%. Therefore, in all patients, independent of the stage of disease, a complete and curative resection should be tried, thus improving the prognosis for a 5-year survival period to 42-57%.3,8,9,11,13,20,22,26 After the cura- tive resection of ACC, disease-free intervals of more than 10 years can be achieved. Because of the poor survival rate in patients with incomplete resections, also in patients with an advanced stage of disease, a curative resection of the primary tumour and of metastases should be performed wherever possible. The overall 5-year survival of patients with stage I or Il of disease is 43-78%, whereas the survival of patients at stage III is 21-27% and at stage IV is only around 0-10%.6,8,11-14,16,22,28 Positive prognostic factors are an early stage and a complete margin-negative resection. The histo- pathological examination according to Harrison revealed a large tumour size, haemorrhage and a high mitotic count, as negative prognostic fac- tors.25 The patient’s age or gender and the
functional status of the tumour have not proven to be significant prognostic factors, only the quality of hormonal secretion influences the survival period according to some reports.5,7,8,11,20,22 When com- paring the 5-year survival one disadvantage is the different distribution of tumour stage between studies. In those excluding patients with an advanced disease from surgical therapy, the survi- val rate is superior. However, when identical groups are compared the survival rate reported here is superior to most other series. 29
Outcomes
The 5-year survival in ACC is far from cure. The mean disease-free interval, even after curative operation, is approximately 12-22 months. 7,8,13,20 Even after complete surgical excision, 23 to 80% of the patients develop loco-regional relapse or distant metastases. Without further treatment the prognosis is poor.8,11-14,20,23 In the case of loco- regional recurrence re-operation prolongs again the disease-free survival. It is superior (5-year survival rate 27-57%) to chemotherapy (5-year survival rate of 0-8%). Additionally, re-operation provides excel- lent palliation, especially in tumours associated with symptomatic hormone production. 8,11,13,20,22 Even in patients with recurrent loco-regional dis- ease, a long-term survival of over 10 years can be achieved with repeated re-operation. The high rate of recurrent disease, even in patients with a curative resection, emphasises the necessity for a careful clinical, endocrinologic and radiographic follow-up. In functioning ACC’s the concentration of hormones or precursors can be utilised as a tumour marker in the post-operative period.3 Although the prognosis of patients with ACC is poor, our results show that radical and if necessary repeated resection is the most successful therapy.
References
1. Lipsett MB, Hertz R, Ross GT. Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 1963;35: 374-383.
2. Hutter AM, Kayhoe DE. Adrenal cortical carcinoma. Clinical features of 138 patients. Am J Med 1966;41:572-580.
3. Schulick RD, Brennan MF. Adrenocortical carcinoma. World J Urol 1999; 17:26-34.
4. Dackiw APB, Lee JE, Gagel RF, Evans DB. Adrenal cortical carcinoma. World J Surg 2001;25:914-926.
5. Cohn K, Gottesman L, Brennan M. Adrenocortical carcinoma. Surgery 1986; 100:1170-1177.
6. Bodie B, Novick AC, Pontes JE et al. The Cleveland clinic experience with adrenal cortical carcinoma. J Urol 1989; 141:257-260.
7. Luton JP, Cerdas S, Billaud L et al. Clinical features of
adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990; 322:1195-1201.
8. Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C. Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French association of endocrine surgery. Surgery 1992;112:972-980.
9. Soreide JA, Brabrand K, Thoresen SO. Adrenal cortical carcinoma in Norway, 1970-1984. World J Surg 1992; 16: 663-668.
10. Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, Makowska AM. Adrenocortical carcinoma. A clinical study and treat- ment results of 52 patients. Cancer 1995;75:2587-2591.
11. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P. The Italian registry for adrenal cortical carcinoma: analysis of a multiinstitutional series of 129 patients. Surgery 1996; 119:161-170.
12. Barzon L, Fallo F, Sonino N, Daniele O, Boscaro M. Adrenocorical carcinoma: experience in 45 patients. Oncol- ogy 1997;54:490-496.
13. Bellantone R, Ferrante A, Boscherini M et al. Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma. Surgery 1997; 122: 1212-1218.
14. Chapuis Y, Icard P, Barei R et al. Possibilités et limites du traitement chirurgical des cortico-surrénalomes malins. À propros d’une série de 74 cas. Chirurgie 1998; 123:61-6.
15. Wajchenberg BL, Pereira MAA, Medonca BB et al. Adreno- cortical carcinoma: clinical and laboratory observations. Cancer 2000;88:711-736.
16. Icard P, Goudet P, Charpenay C et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French association of endocrine surgeons study group. World J Surg 2001;25:891-897.
17. Hsing AW, Nam JM, Chien HTC, Mclaughlin JK, Fraumeni JF. Risk factors for adrenal cancer: an exploratory study. Int J Cancer 1996;65:432-436.
18. Gicquel C, Baudin E, Lebouc Y, Schlumberger M. Adrenocor- tical carcinoma. Ann Oncol 1997;8:423-427.
19. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-169.
20. Pommier R, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992; 112:963-971.
21. Wooten MD, King DK. Adrenal cortical carcinoma: epi- demiology and treatment with mitotane and a review of the literature. Cancer 1993;72:3145-3155.
22. Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocor- tical carcinoma. Ann Surg Oncol 1999;6:719-726.
23. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003; 169:5-11.
25. Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 1999; 134:181-185.
26. Grondal S, Cedermark B, Eriksson B et al. Adrenocortical carcinoma. A retrospective study of a rare tumor with a poor prognosis. Eur J Surg Oncol 1990; 16:500-506.
27. Hedican SP, Marshall FF. Adrenocortical carcinoma with intracaval extension. J Urol 1997; 158:2056-2061.
28. Zografos GC, Driscoll D, Karakousis C, Rao U, Huben R. Staging and grading in the survival of adrenal carcinomas. Eur J Surg Oncol 1994; 20:449-453.
29. Langer P, Bartsch D, Moebius E, Rothmund M, Nies C. Adrenocortical carcinoma-our experience with 11 cases. Langenbeck’s Arch Surg 2000; 385:393-397.