SURGERY TODAY Springer 2007
Combined Liver and Inferior Vena Cava Resection for Adrenocortical Carcinoma
SUSUMU OHWADA1, MASARU IZUMI2, YOSHIFUMI TANAHASHI1, SUSUMU KAWATE1, KUNIHIRO HAMADA1,
HIROFUMI TSUTSUMI1, JUN HORIGUCHI1, YUKIO KOIBUCHI1, TORU TAKAHASHI1, and MASANOBU YAMADA3
Departments of 1Surgery and 3Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan
2 Department of Surgery, Sudo Hospital, Annaka, Gunma, Japan
Abstract
Purpose. Adrenocortical carcinoma (ACC) is a rare malignancy, usually diagnosed at an advanced stage when it has invaded or adhered to adjacent organs. We report our experience of performing combined liver and inferior vena cava (IVC) resection for ACC.
Methods. Six patients with clinical stage III (n = 4) or IV (n = 2) ACC underwent combined resection of the liver and IVC. Two patients underwent extended right hepatectomy, and four underwent segmentectomy. In four patients, the IVC was resected segmentally: it was replaced with expanded polytetrafluoroethylene (ePTFE) in three of these patients, and not recon- structed in one. In two patients, the IVC was partially resected and closed directly.
Results. Perioperative mortality was zero, and morbid- ity was 33.3%, with temporary liver failure in two pa- tients and renal failure in one patient. Recurrence was found within 8.1 months in three (50%) of the six pa- tients. The mean recurrence-free survival period was 20.1 ± 7.7 months (95% confidence interval [CI]: 5.1- 35.4), and the median survival time was 6.1 ± 9.8 months (95% CI: 00-25.3). The 5-year disease-free survival rate was 16.7%.
Conclusions. Patients with ACC involving both the liv- er and IVC are candidates for partial hepatectomy and segmental IVC resection. Resection affords the possi- bility of negative margins, acceptable perioperative morbidity and mortality, and prolonged survival in some patients.
Key words Adrenocortical carcinoma · Inferior vena cava replacement · Liver resection · Inferior vena cava resection
Introduction
Adrenocortical carcinoma (ACC) is relatively rare and most cases are diagnosed at an advanced stage, with invasion of or adherence to the liver, kidney, and infe- rior vena cava (IVC).1 Complete surgical resection is the treatment of choice for ACC,2 and a margin-free resection (R0 resection) is a strong predictor of long- term survival.3-5 Stage III and IV tumors defined by in- vasion of or adherence to adjacent organs often require en bloc resection of the liver, IVC, kidney, spleen, and pancreas to achieve R0 resection and prevent tumor spillage.5 In the past, patients with ACC involvement of the IVC were considered poor candidates for surgery; however, the development of innovative surgical tech- niques for liver tumors involving the IVC6-10 has result- ed in a curative surgical approach for tumors involving both the liver and IVC. We report our experience of performing combined liver and IVC resection for stage III and IV ACC.
Patients and Methods
Clinical Evaluation and Staging
Six patients underwent resection of ACC between 1993 and 2005 at Gunma University Hospital and its affili- ates, in Japan. There were three women and three men, with a median age of 56.3 years (range, 43-68 years). One (16.7%) woman had Cushing’s syndrome and one (16.7%) woman had hypertension. Two patients had edema of the lower extremities. In four patients, the tumors were nonfunctioning and detected on screening computed tomography (CT) images done for other rea- sons. The right adrenal gland was involved in all pa- tients. The mean tumor diameter was 14cm [range, 7-20 cm; being <10cm in two patients (40%) and >15 cm in four patients (60%)]. Locoregional invasion was
| Patient | Age (years) | Sex | Symptoms | Previous history | Tumor location | Elevated hormones | Cushing's syndrome | Clinical | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Tumor size (cm) | T | N | M | Stagingª | ||||||||
| 1 | 61 | M | — | — | Right | No | 8 | T4 | 0 | 0 | III | |
| 2 | 47 | F | — | Myoma uteri | Right | No | 18 | T4 | 0 | 0 | III | |
| 3 | 68 | M | — | — | Right | No | 16 | T4 | 0 | 0 | III | |
| 4 | 62 | M | Weight loss | — | Right | No | 20 | T4 | 0 | 0 | III | |
| Lower | ||||||||||||
| extremities edema | ||||||||||||
| 5 | 57 | F | Hypertension | Cortical adenoma | Right | 17-OHCS 17-KS | Preclinical | 7 | T4 | 0 | Liver | IV |
| 6 | 43 | F | Moon face Lower extremities edema | — | Right | 17-OHCS 17-KS DHEA | Clinical | 15 | T4 | 0 | Lung Liver | IV |
Patient # 6 had tumor thrombi in the inferior vena cava
17-OHCS, hydroxycorticosterone; 17-KS, ketosteroid; DHEA, dehydroepiandrosterone
a According to Lee et al.11
present in all six patients, and synchronous distant me- tastases were found at the time of presentation in two (33.3%) patients. Clinically, four (66.6%) patients had stage III disease and two (33.3%) had stage IV disease (Table 1).11
Surgery
The surgical procedure for liver and IVC resection is described elsewhere.8 Briefly, the arteries supplying the tumor, including the adrenal, phrenic, lumbar, and renal arteries, were ligated and the para-aortic and hepatic hilar lymph nodes were resected. If the renal arteries or veins were involved, nephrectomy was required. Liver resection was performed anatomically, according to Couinaud’s liver segments, after ligating the inflow arteries and portal branches to be resected. The liver parenchyma was divided using an ultrasonic surgical aspirator (CUSA EXcel Radionics, Burlington, MA, USA) and bipolar cautery with a saline irrigation sys- tem. Hemihepatic vascular occlusion or selective inflow occlusion was done to minimize blood loss during he- patic parenchymal resection. Occlusion was continued for 20 min, followed by release for 5 min, which was re- peated until the liver parenchyma was resected. To ex- pose the supra- to retrohepatic IVC, we used an anterior transhepatic approach, dividing the liver parenchyma first. The supra- or retrohepatic IVC just below the hepatic venous confluence was clamped to ensure that both the mean arterial and central venous pressures were maintained following intravenous hydration. Veno-venous bypass with a centrifugal pump was used for patients with a 30% drop in mean arterial pressure
and those who we thought may require vascular exclu- sion for longer than 60 min. After en bloc resection of the tumor, bile leakage from the transected surface of the liver was tested, and an external drainage tube was inserted into the bile duct. An 18- to 22-mm expanded polytetrafluoroethylene (ePTFE) graft was used if IVC replacement was required. The ePTFE graft was over- lapped using an omental pedicle. Patients who under- went ePTFE replacement received low-dose heparin postoperatively and then warfarin to give a prothrom- bin time/international normalized ratio (PT/INR) of around 2.3 for the first 3 months. Long-term anticoagu- lation was maintained with a single aspirin tablet daily thereafter.
Statistical Analysis
Statistical analyses were done using the program SPSS (SPSS, version 11.0J, Tokyo, Japan). Disease-free and overall survival curves were generated using the Kaplan-Meier method.
Results
Surgical Results
We used a transabdominal approach in four patients, and a thoracoabdominal approach in two patients. Two patients underwent extended right hepatectomy, and four patients underwent segmentectomy of the posteri- or segment in three patients; and S4a, S5, and S6 in one patient. Two patients underwent right nephrectomy and
one patient underwent portal vein resection and re- construction, extrahepatic bile duct resection, and hepaticojejunostomy. The IVC was resected segmen- tally in four patients and partially in two patients. After segmental IVC resection, the IVC was replaced with an ePTFE graft in three of the four patients and it was not reconstructed in the other one. Although ePTFE replacement was indicated in one of the other patients, the procedure was contraindicated because of the high risk of liver failure and expected hepaticojejunos- tomy leakage with extended hepatectomy, massive bleeding, and a low postoperative indocyanine green (ICG) K value.12 The IVC was closed directly in the two patients undergoing partial IVC resection. An active venovenous bypass was done in one patient, and another patient required aortic cross-clamping below the superior mesenteric artery. We performed lymphadenectomy and R0 resection in all six patients. The average operating time was 10h 35 min (range, 5h 5min to 20h) and the average blood loss was 5187 ml (range, 779-17483ml). Two of the patients who underwent combined resection of the IVC and extended right hepatectomy suffered postoperative
complications including hyperbilirubinemia, hepatic failure, acute renal failure, and lower extrimities edema (Table 2). There was no operative or hospital death. None of the IVC grafts became infected and they were still patent at the last follow-up. The typical CT findings of stage III ACC and the en bloc resected specimen from patient 4 are shown in Fig. 1.
Pathological Results
R0 resection was confirmed histopathologically in all six patients. We found extra-capsular invasion in all pa- tients, which involved the IVC and liver in four patients each. Three patients had both liver and IVC invasion. The patient who underwent combined liver and IVC resection had no pathological extra-adrenal invasion and all but one patient had vascular invasion. One pa- tient had a sarcoma-like component. The mitotic index ranged from 2 to 30/10 high power fields (HPF). The resection margins were microscopically clear of tumor cells in all patients. The clinical and pathological stages were the same (Table 3).
A
B
Tumor
Liver -
IVC
Kidney
+
Ureter
C
| Patient | Combined resection | Liver resectionª | IVC resection/repair | Bypass | LN resection | Duration of operation (min) | Blood loss (ml) | Postop. K value | Morbidity |
|---|---|---|---|---|---|---|---|---|---|
| 1 | IVC | S6, S7 | Direct closure | No | Yes | 305 | 779 | — | None |
| 2 | IVC | S6, S7 | Direct closure | No | Yes | 515 | 1 250 | 0.142 | None |
| 3 | IVC, Kidney | S6, S7 | ePTFE | No | Yes | 600 | 2510 | 0.180 | None |
| 4 | IVC, Kidney | S4a, S5, S6 | No reconstruction | Nob | Yes | 1200 | 17 483 | 0.072 | Hyperbilirubinemia |
| Portal vein | S7, S8 | Lower extremities edema | |||||||
| Bile duct | Ascites | ||||||||
| Hepaticojejunostomy leakage Acute renal failure | |||||||||
| 5 | IVC | S4a, S5, S6 | ePTFE | No | Yes | 650 | 3030 | 0.159 | None |
| 6 | IVC | S4a,S5, S6 | ePTFE | Biopump | Yes | 540 | 6070 | 0.137 | Hyperbilirubinemia |
| S7, S8 | Ascites |
ePTFE, expanded polytetrafluoroethylene; IVC, inferior vena cava; LN, lymph node
a Couinaud segment
b Aortic half clamp
Fig. 2. Cumulative recurrence curve
20
40
60
80
100
0
0
%
6
12
18
24
30
36
42
48
months
Survival and Recurrence
None of the patients received adjuvant mitotane thera- py or radiation therapy. The median follow-up period was 33.4 months (range, 11.4 to 57.6 months). The most frequent site of metastasis was the lung, seen in four patients. Liver and locoregional recurrences were also seen in one patient each. These metastases were unre- sectable because of bulky local recurrence or dissemi- nated distant metastasis. Later, brain and bone metastasis occurred (Table 3). Recurrence developed within 8.1 months in three (50%) of the six patients. The cumula- tive recurrence curve is shown in Fig. 2. The mean re- currence-free survival time was 20.1 ± 7.7 months (95% confidence interval [CI]: 5.1-35.4), and the median survival time was 6.1 ± 9.8 months (95% CI: 00-25.3). The 5-year disease-free survival rate was 16.7%. Five patients were treated with mitotane (o,p’DDD; o,p’- dichlorodiphenyldichloroethane) with or without chemotherapy after tumor recurrence. Subsequently, cytotoxic agents were administered. The mean overall survival time for all patients was 33.5 ± 8.6 months (95% CI: 17.6-49.3), and the median survival time was 25.0 ± 11.1 months (95% CI: 3.2-46.8).
Discussion
We reported 20% mortality in a previous series of pa- tients who underwent combined liver and IVC resec- tion.8 Conversely, there was no mortality in this series, although two patients who underwent extended right hepatectomy and IVC resection suffered postoperative liver failure. The reported perioperative mortality rate ranges from 11% to 25% in series of combined liver and IVC resection.9,13 The operative mortality rate for ACC resection was 5.5% in one recent study,5 and aggressive surgery for ACC with extension into the IVC was asso- ciated with a 10%-15% mortality rate14 in another study. Both cortisol and androgen excess may be re-
| Patient | Pathology | Site of recurrence | Time to recurrence (months) | Outcome (months) | ||
|---|---|---|---|---|---|---|
| T | N | Staging | ||||
| 1 | T4 | — | III | Lung | 5.6 | Died (34.2) |
| 2 | T4 | 0 | III | No recurrence | — | Alive (48.9) |
| 3 | T3 | 0 | III | Lung | 36.5 | Alive (50.5) |
| 4 | T4 | 0 | III | Local | 6.1 | Alive (9.5) |
| 5 | T4 | 0 | IV | Lung, Liver | 3 | Died (15.9) |
| 6 | T4 | 0 | IV | Lung, Liver, Brain, Bone | 21.7 | Died (23.7) |
sponsible for an increased risk of perioperative cardio- vascular events. Furthermore, combined resection of the IVC and liver is a considerable operative challenge, with high mortality and morbidity rates. The keys to the success of such aggressive surgery are precise evalua- tion of the tumor extension and careful monitoring of the functions of the liver, kidneys, and adrenal hor- mone. When extensive liver resection is planned, even if the liver is normal, the remnant functional reserve is critical. We have found that perioperative real-time monitoring of ICG-K, measured using pulse spectro- photometry, is useful for evaluating the remnant liver functional reserve before, during, and after liver resec- tion for hepatocellular carcinoma associated with cir- rhosis.12 We even use this measure to evaluate extensive liver resection of the normal liver.
In combined resection of the IVC and liver, all blood flowing to the tumor, IVC, and liver should be con- trolled as well as possible to obtain a bloodless field and minimize blood loss. We used an anterior approach to liver resection to expose the supra- to retrohepatic IVC.8 One patient suffered a massive bleed from the right hepatic vein soon after parenchymal transection of the extended right hepatectomy, leaving the IVC, tumor, and a bare area connected. A possible explana- tion for this was that inflow from a feeding lumbar, adrenal, or phrenic artery had not been controlled com- pletely, resulting in very rapid congestion of the liver, and the increased hepatic venous pressure caused the clamp to slip off. This situation required temporary half- clamping of the descending aorta. Clamping of the de- scending aorta15 and the introduction of an occlusion balloon catheter (Baxter, Deerfield, IL, USA) near the diaphragm16 are alternative methods for controlling massive bleeding from major vessels. The surgical ap- proach should be flexible enough to adopt any of these variations and allow innovation in each patient.
There is no definite indication for reconstruction af- ter resecting the retro- to suprahepatic IVC. The IVC can be repaired primarily if the resected segment is small. The suprarenal IVC may be ligated safely when the IVC collaterals, including the vertical vein systems, azygos, and hemi-azygos veins, are well developed.
Acute renal failure occurred in one patient (No. 4) who did not undergo reconstruction of the IVC, as reported elsewhere.17 Larger segmental resections of the IVC should be reconstructed with synthetic or autogenous grafts.8,10 A ringed 18- to 20-mm ePTFE is currently our graft of choice. Although prosthetic material is associ- ated with a risk of infection, there was no incidence of graft infection in this or our previous series 8, as re- ported elsewhere.10,13
We used an omental wrap for prosthetic caval grafts when performing combined liver resection and caval reconstructions, because the omentum has the capacity for absorption, adhesion formation, neovascularization, and infection defense.13,18,19 We also inserted an external drainage tube in the bile duct through the cystic duct and sealed both the transected hepatic surface and the graft with fibrin glue, to protect the graft from bile leak- age.8 We used low-dose perioperative heparin, followed by warfarin, and then long-term maintenance aspirin. With this regimen, all grafts remained patent.
It remains unclear if surgical treatment should be at- tempted in patients with bulky T4 invading the liver and IVC, or stage IV metastatic disease and IVC extension. Complete tumor removal (R0 resection) offers by far the best chance for long-term survival, making surgery the treatment of choice for stage I-III ACC.3-5,20-22 The reported 5-year survival rates for stages I, II, III, and IV are 66%, 58%, 24%, and 0%, respectively.5 Accord- ing to past reports, patients who underwent complete resection of the primary tumor had 5-year survival rates of 3%-55%, whereas those with incomplete resection had 5-year survival rates of 0%-9%.20,21,23,24 The poorer survival of patients with stage III or IV disease is at- tributable to the incomplete resection of bulky T4 or metastatic disease.
Our small series showed that combined and complete resection of the liver, kidney, and IVC, aiming at com- plete resection, was feasible with acceptable morbidity. The 5-year disease-free survival rate was 16.7%, and the mean recurrence-free survival period was 20.1 ± 7.7 months. These survival rates are similar to those in a previous series, in which patients with stage III or IV disease had a median survival period of 15 months and
a 5-year survival rate of 10%.21 Our two patients with stage IV ACC, who underwent resection of the primary tumor and metastases, survived for 16.1 months and 25.2 months, respectively, although mitotane was ad- ministered after recurrence. Conversely, patients who undergo debulking surgery and those who do not un- dergo surgery at all have a dismal outcome. According to previous reports, patients who did not undergo sur- gery died within 12 months,21 and patients who under- went debulking or no surgery survived for only 8.6 ± 5.9 months.25 Moreover, the 5-year survival rate of patients with stage IV disease was 0%-9%,5,20,23,24 and the mean survival period was 7-8 months.5,23 In comparing the survival in our series and those in these reports, we be- lieve that the survival benefits justify complete resection for bulky T4 tumors, including the liver and IVC, and the resection of metastases. Furthermore, there are promising reports that aggressive surgery prolonged survival. Surgical resection of residual disease after eto- poside, doxorubicin, and cisplatin (EDP) plus mitotane chemotherapy in patients who would not tolerate radi- cal surgery has also achieved good results.26 Considering that patients who underwent a complete second resec- tion of locally recurrent or distant metastatic disease had a median survival time of 74 months and 5-year survival of 57%,21 if surgery of the IVC allows complete resection of the primary tumor and its locoregional ex- tension, involvement of the IVC should not be consid- ered a contraindication for surgery.
Another concern is the operative mortality and mor- bidity of aggressive surgery. Although our series had 0% mortality and 33% (2/6) morbidity, the reported mortality is high, ranging from 10% to 15% for patients undergoing surgery for ACC with both metastatic dis- ease and IVC extension, and from 11% to 25% for those undergoing combined liver and IVC resection.9,13 Therefore, aggressive surgery should be restricted in patients with severe comorbidity or unresectable meta- static disease.
Recurrence was found within 8.1 months in three of our six patients and after a longer period in the other three. ACC may have two different types of tumor biol- ogy, leading to early or late recurrence after resection, and this might depend on the biological aggressiveness of the tumor. The presence of a stage III tumor, a tumor diameter greater than 12cm, a high mitotic index, ab- normal mitotic figures, and intratumor hemorrhage are all reported to be high-risk factors for recurrence.27-29 We need to consider adjuvant therapy after surgical re- section for high-risk patients and patients with bulky T4 invading the liver and IVC, or metastatic disease, al- though the effects of adjuvant therapy with mitotane alone have not been established.5 Interestingly, the sur- vival rate in a small series of patients with stage III ACC treated by postoperative radiotherapy was higher than
expected.30 Based on its response rate, EDP plus mito- tane shows promise as combination therapy for high- risk patients with ACC in an adjuvant setting.
Acknowledgment. We thank Hiroyuki Toya, MD and Nozomi Togo, MD for the pathological analysis. This work was supported in part by the Harunasou Foundation Fund subsidizing Cancer Research, the Kanetsu Chuo Hospital Research Fund, and the Research Fund of the Uchida Clinic in Inamachi, Saitama.
References
1. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195-201.
2. Dackiw AP, Lee JE, Gagel RF, Evans DB. Adrenal cortical carcinoma. World J Surg 2001;25:914-26.
3. Khorram-Manesh A, Ahlman H, Jansson S, Wangberg B, Nilsson O, Jakobsson CE, et al. Adrenocortical carcinoma: surgery and mitotane for treatment and steroid profiles for follow-up. World J Surg 1998;22:605-11; discussion 611-2.
4. Kendrick ML, Lloyd R, Erickson L, Farley DR, Grant CS, Thompson GB, et al. Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 2001;136:543-9.
5. Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, 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- 7.
6. Yamaoka Y, Ozawa K, Kumada K, Shimahara Y, Tanaka K, Mori K, et al. Total vascular exclusion for hepatic resection in cirrhotic patients. Application of venovenous bypass. Arch Surg 1992;127: 276-80.
7. Hannoun L, Delriviere L, Gibbs P, Borie D, Vaillant JC, Delva E. Major extended hepatic resections in diseased livers using hypothermic protection: preliminary results from the first 12 patients treated with this new technique. J Am Coll Surg 1996;183: 597-605.
8. Ohwada S, Ogawa T, Kawashima Y, Ohya T, Kobayashi I, Tomizawa N, et al. Concomitant major hepatectomy and inferior vena cava reconstruction. J Am Coll Surg 1999;188:63-71.
9. Lodge JP, Ammori BJ, Prasad KR, Bellamy MC. Ex vivo and in situ resection of inferior vena cava with hepatectomy for colorec- tal metastases. Ann Surg 2000;231:471-9.
10. Hemming AW, Reed AI, Langham MR, Jr., Fujita S, Howard RJ. Combined resection of the liver and inferior vena cava for hepatic malignancy. Ann Surg 2004;239:712-9; discussion 719-21.
11. Lee JE, Berger DH, el-Naggar AK, Hickey RC, Vassilopoulou- Sellin R, Gagel RF, et al. Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 1995; 118:1090-8.
12. Ohwada S, Kawate S, Hamada K, Yamada T, Sunose Y, Tsutsumi H, et al. Perioperative real-time monitoring of indocyanine green clearance by pulse spectrophotometry predicts remnant liver functional reserve in resection of hepatocellular carcinoma. Br J Surg 2006;93:339-46.
13. Sarmiento JM, Bower TC, Cherry KJ, Farnell MB, Nagorney DM. Is combined partial hepatectomy with segmental resection of inferior vena cava justified for malignancy? Arch Surg 2003; 138:624-30; discussion 630-1.
14. Chiche L, Dousset B, Kieffer E, Chapuis Y. Adrenocortical car- cinoma extending into the inferior vena cava: presentation of a 15-patient series and review of the literature. Surgery 2006;139: 15-27.
15. Ruel M, Bedard P, Morash CG, Hynes M, Barber GG. Resection of right atrial tumor thrombi without circulatory arrest. Ann Thorac Surg 2001;71:733-4.
16. Shinghal R, Vricella LA, Mitchell RS, Presti J, Jr. Cavoatrial tumor thrombus excision without circulatory arrest. Urology 2003;62:138-40.
17. Huguet C, Ferri M, Gavelli A. Resection of the suprarenal infe- rior vena cava. The role of prosthetic replacement. Arch Surg 1995;130:793-7.
18. Liebermann-Meffert D. The greater omentum. Anatomy, embry- ology, and surgical applications. Surg Clin North Am 2000;80:275- 93, xii.
19. Shrager JB, Wain JC, Wright CD, Donahue DM, Vlahakes GJ, Moncure AC, et al. Omentum is highly effective in the manage- ment of complex cardiothoracic surgical problems. J Thorac Cardiovasc Surg 2003;125:526-32.
20. 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. The ACC Italian Registry Study Group. Surgery 1996;119:161-70.
21. Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical car- cinoma. Ann Surg Oncol 1999;6:719-26.
22. Allolio B, Hahner S, Weismann D, Fassnacht M. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2004;60:273- 87.
23. Zografos GC, Driscoll DL, Karakousis CP, Huben RP. Adrenal adenocarcinoma: a review of 53 cases. J Surg Oncol 1994;55: 160-4.
24. Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-51.
25. Tauchmanova L, Colao A, Marzano LA, Sparano L, Camera L, Rossi A, et al. Andrenocortical carcinomas: twelve-year prospec- tive experience. World J Surg 2004;28:896-903.
26. Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treat- ment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 2005;12:657-66.
27. Weiss LM, Medeiros LJ, Vickery AL, Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-6.
28. Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical carcinoma after cura- tive resection. Arch Surg 1999;134:181-5.
29. Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002;20:941-50.
30. Markoe AM, Serber W, Micaily B, Brady LW. Radiation therapy for adjunctive treatment of adrenal cortical carcinoma. Am J Clin Oncol 1991;14:170-4.