ADRENOCORTICAL CARCINOMA INVADING THE INFERIOR VENA CAVA: CASE REPORT AND LITERATURE REVIEW
James J. Mezhir, MD,1 Jie Song, MD,5 Giancarlo Piano, MD,2 2
Guiliano Testa, MD,” Jaishankar Raman, MD, PhD,4 Hikmat A. Al-Ahmadie, MD,”
5 and Peter Angelos, MD, PhD1
ABSTRACT
Objective: To present the case of a man with a right- sided adrenocortical carcinoma that invaded the inferior vena cava and was managed by radical resection and vein patch repair.
Methods: We report the clinical, laboratory, imaging, and operative findings, and we highlight the pertinent fea- tures of this case. The literature is reviewed for the man- agement of adrenocortical carcinoma in conjunction with inferior vena cava invasion.
Results: In a 34-year-old man with new-onset abdom- inal pain, abdominal imaging disclosed a large right adre- nal mass with invasion into the inferior vena cava. Laboratory values revealed that the adrenal mass was like- ly nonfunctional. At surgical intervention with use of car- diopulmonary bypass, the mass was removed en bloc with the adrenal gland, right kidney, and the wall of the inferi- or vena cava, and the inferior vena cava was reconstructed with bovine pericardium.
Conclusion: Despite direct invasion or extension of tumor thrombus into the inferior vena cava (or both), com- plete (R0) resection can be obtained. Thus, this scenario should not preclude attempted curative resection in patients with adrenal cancer. (Endocr Pract. 2008;14: 721-725)
Abbreviations:
ACC = adrenocortical carcinoma; CPB = cardiopul- monary bypass; IVC = inferior vena cava
From the Department of Surgery, Sections of 1General Surgery, 2Vascular, 3Transplant, and 4Cardiac Surgery, and 5Department of Pathology, University of Chicago Medical Center, Chicago, Illinois.
Address correspondence and reprint requests to Dr. Peter Angelos, Department of Surgery, Section of General Surgery, University of Chicago Medical Center, 5841 South Maryland Avenue, Mail Code 4052, Chicago, IL 60637.
@ 2008 AACE.
CASE REPORT
A 34-year-old healthy man presented with abdominal pain of recent onset. Computed tomography with use of an intravenous contrast agent revealed a right adrenal mass measuring 5.3 by 6.6 cm with invasion into the inferior vena cava (IVC) (Fig. 1). The extent of tumor invasion appeared to be at the level of the hepatic veins superiorly and above the renal veins inferiorly. There was no evi- dence of metastatic disease or intra-abdominal or retroperitoneal lymphadenopathy. Laboratory values for plasma free metanephrines, aldosterone, potassium, and testosterone were all within normal limits.
The patient underwent surgical exploration through a right thoracoabdominal incision that extended from the midline to the right costal margin into the eighth inter- space. There was no gross evidence of disease outside the adrenal gland. A large adrenal mass with direct invasion into the IVC was found (Fig. 2 A). The invasion of the IVC appeared to be directly through the adrenal vein, and there appeared to be no free floating tumor thrombus in the vena cava. Transesophageal echocardiography was performed and confirmed the absence of tumor thrombus in the right atrium. The diaphragm was taken down and the liver was mobilized for complete exposure of the retrohepatic IVC. Distal control of the IVC was obtained in its infrarenal por- tion. With the patient on cardiopulmonary bypass (CPB), straight vascular clamps were applied on the IVC while the hepatic vein outflow was left free; thus, portal flow bypass was avoided. The right kidney and the wall of the IVC were resected en bloc with the adrenal gland and associat- ed mass. The IVC was reconstructed with a bovine peri- cardial patch (Fig. 2 B). No intraoperative complications or blood transfusions were required; the patient was dis- charged home on postoperative day 8 without morbidity.
The final pathology analysis revealed a 132-g tumor (7.0 by 6.0 by 2.5 cm) with extension into the IVC mea- suring 3 cm in greatest dimension. Two periadrenal lymph nodes were without evidence of metastatic carcinoma, and the resection margins were free of tumor. Microscopically, the tumor was composed of epithelioid cells with abun- dant eosinophilic cytoplasm growing in large nests and broad sheets. Necrosis, pronounced nuclear atypia, high mitotic activity, and atypical mitotic figures were noted
A
B
C
D
(Fig. 3 A and B). Invasion into the adrenal parenchyma was also present. Immunohistochemical studies were pos- itive for calretinin (Fig. 3 C), melan-A (Fig. 3 D), inhibin, synaptophysin, and CD56 but negative for chromogranin and cytokeratin. The histopathologic features and immunohistochemical pattern were diagnostic for adreno- cortical carcinoma (ACC) (1,2).
The patient refused adjuvant mitotane therapy. He has participated in monthly follow-up clinic visits and has returned to his premorbid level of functioning. Six months after resection, a surveillance computed tomographic scan
detected a pulmonary nodule, and thoracoscopic resection confirmed the presence of metastatic disease. Currently, the patient remains asymptomatic and is receiving mitotane-based therapy.
DISCUSSION
Adrenocortical carcinoma is a rare, aggressive malig- nant tumor accounting for less than 1% of adrenal masses and 0.02% of all cancers reported annually (3-5). Complete surgical resection remains the most effective
A
B
treatment and, along with early stage, is among the strongest predictors of overall survival (6-8). Up to 40% of adrenal tumors are nonfunctional and thus manifest late during the course of disease as a large mass causing early satiety, weight loss, or abdominal pain. These lesions are frequently found during imaging for other complaints and are often unresectable because of large size and local inva- sion (3,9). The general strategy of surgical therapy for ACC is en bloc resection, which often includes nearby kidney, liver, pancreas, spleen, or bowel. Avoiding dis- ruption of the tumor capsule prevents retroperitoneal seed- ing during resection. Vena cava invasion, which qualifies as stage III disease (10), occurs most commonly with larg- er, right-sided tumors (11). Infrequently, tumor thrombus can extend to the renal vein, IVC, and right atrium without invading the vascular endothelium (12). In these cases, extensive thrombectomy has been advocated, which is extrapolated from experience with renal cell carcinoma (13).
Vena cava extension from ACC was first reported in 1972, and approximately 127 cases have thus far been documented (14,15). In the largest report to date, Chiche et al (14) described 15 patients with ACC and IVC exten- sion treated during a 25-year period, and they also reviewed an additional 106 cases from the world literature. The majority of patients had right-sided tumors and either suprahepatic or retrohepatic caval extension. Seven patients had stage IV disease at the time of resection, whereas the others had local or lymph node involvement without distant disease and were classified as having stage III ACC (10). Most patients required sternotomy in addi- tion to a laparotomy (subcostal or midline) for exposure during resection. Hypothermic circulatory arrest, CPB, hepatic vascular exclusion, and IVC cross-clamping were the methods used for vascular control. Thrombectomy was performed in 13 of 15 patients, and the other 2 underwent IVC resection. Concomitant hepatic resection for metastat- ic disease was performed in 4 patients, and 3 patients had
incomplete resections. There were 2 perioperative deaths (13%). All patients received adjuvant mitotane therapy. Median survival of the 13 surviving patients was 8 months (mean follow-up, 15.3 months; range, 4 to 45). At follow- up, 3 patients were alive at 24, 25, and 45 months, respec- tively, after resection.
In their literature review of 106 patients, as with their own cohort, Chiche et al (14) found that the majority of patients had right-sided tumors. Of the 76 patients who underwent surgery, thrombectomy was the treatment modality in 56 cases, partial IVC resection in 15, complete IVC resection and reconstruction in 3 cases, and biopsy without resection owing to inoperability in 2 cases; 28 patients had extension of thrombus to the right atrium. The majority of patients underwent CPB. Follow-up informa- tion was available in 65 patients; 24 patients died after a median survival time of 9 months. Twelve patients were alive at ≥24 months after resection.
Ohwada et al (15) described 4 patients with stage III and 2 patients with stage IV ACC who required both IVC and hepatic resection to achieve “negative” margins. All patients had right-sided tumors, ranging from 7 cm to 20 cm. Only 1 patient required venovenous bypass. Recon- struction of the IVC with synthetic graft was required in 3 patients, and 2 IVC defects were repaired by direct clo- sure; 1 patient did not require repair. There were no peri- operative deaths. All margins were pathologically negative, and no patients received adjuvant mitotane ther- apy until disease recurrence. At a median follow-up of 33 months (range, 11 to 58), the overall disease-free survival rate was 16.7%, and the median survival was 25 months. All patients alive at follow-up had stage III disease. One patient was alive without recurrence at 49 months, anoth- er was alive but with lung metastatic lesions at 51 months (time to recurrence was 37 months), and the third patient had a local recurrence at 6 months and was alive 10 months after resection.
A
B
C
D
Both of these foregoing studies highlight the critical aspects of the approach to patients with ACC and IVC involvement (14,15). Hormonal studies should be per- formed because 60% of adrenal cancers are functional (5). Computed tomography with venous phase imaging has supplanted the use of venography for assessment of the extent of IVC invasion or thrombus (or both) (16). Magnetic resonance imaging and, in some cases, positron emission tomography and functional nuclear medicine imaging are indicated if the pathogenesis of the adrenal mass is in question (17). Determining the presence and extent of tumor thrombus is critical, inasmuch as this may prevent cross-clamping over thrombus and thus avoid tumor embolization. This information also helps in plan- ning the operative approach, which includes the type and extent of incision in addition to the potential need for CPB. Methods for vascular control depend on the location and extent of IVC thrombus. For suprahepatic and retro- hepatic lesions, patients are more likely to require CPB if thrombectomy is not feasible. In our patient, preoperative imaging suggested that the extent of tumor thrombus or invasion was at the level of the hepatic veins; consequent- ly, CPB was used. True retrohepatic lesions without tumor
thrombus do not routinely necessitate the use of CPB (14,15).
Potential incisions for exploration include midline laparotomy with or without sternotomy, bilateral or unilat- eral subcostal incisions, thoracoabdominal incisions, or any combination. Inferior vena cava reconstruction in the setting of resection for a malignant tumor has been report- ed previously (18,19). Polytetrafluoroethylene, autolo- gous, and bovine pericardial (20) grafts have been used for vein patching or reconstruction; reported graft patency rates have been as high as 67% at 5 years (19). The com- bination of liver resection and IVC reconstruction has also been reported, with perioperative mortality rates of 6% to 9% (21,22). The use of adjuvant therapy for patients with ACC remains to be elucidated, but retrospective data have shown a benefit associated with mitotane therapy after complete (R0) resection (23).
CONCLUSION
Patients with ACC and IVC invasion represent a rare cohort, but with a potential for improved outcomes when appropriate selection of patients is used for interventions.
Some of the largest experiences with ACC to date report 5-year survival rates as high as 47% after R0 resection and a median survival of 9 months if the tumor is unresectable or only palliative measures are possible (6). These out- comes are not replicated in studies in which patients required IVC resection and reconstruction, possibly reflecting the advanced stage and aggressiveness of the disease. Moreover, many of these resections were per- formed to prevent tumor embolization, relieve local symp- toms, or help reduce hormonally active tumor tissue (14). Despite the poor outcome statistics, long-term survival after complete resection is possible in this cohort of patients (14,15). Vena cava resection for locally advanced ACC is feasible and should be attempted to achieve R0 resection, in that it is the only potential for cure and pro- longed survival in these patients.
DISCLOSURE
The authors have no conflicts of interest to disclose.
REFERENCES
1. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002; 26:1612-1619.
2. Zhang PJ, Genega EM, Tomaszewski JE, Pasha TL, LiVolsi VA. The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study. Mod Pathol. 2003;16:591-597.
3. Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin. 1987;37:348-365.
4. Phan AT. Adrenal cortical carcinoma-review of current knowledge and treatment practices. Hematol Oncol Clin North Am. 2007;21:489-507; viii-ix.
5. Rodgers SE, Evans DB, Lee JE, Perrier ND. Adrenocortical carcinoma. Surg Oncol Clin N Am. 2006; 15:535-553.
6. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma [with discussion]. Surgery. 1992;112:963-971.
7. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P (ACC Italian Registry Study Group). The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. Surgery. 1996; 119:161-170.
8. 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.
9. 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.
10. Lee JE, Berger DH, el-Naggar AK, et al. Surgical man- agement, DNA content, and patient survival in adrenal cor- tical carcinoma. Surgery. 1995;118:1090-1098.
11. Hedican SP, Marshall FF. Adrenocortical carcinoma with intracaval extension. J Urol. 1997;158:2056-2061.
12. Shahian DM, Nieh PT, Libertino JA. Resection of atrio- caval adrenal carcinoma using hypothermic circulatory arrest. Ann Thorac Surg. 1989;48:421-422.
13. Bissada NK, Yakout HH, Babanouri A, et al. Long-term experience with management of renal cell carcinoma involving the inferior vena cava. Urology. 2003;61:89-92.
14. Chiche L, Dousset B, Kieffer E, Chapuis Y. Adrenocortical carcinoma extending into the inferior vena cava: presentation of a 15-patient series and review of the literature. Surgery. 2006;139:15-27.
15. Ohwada S, Izumi M, Tanahashi Y, et al. Combined liver and inferior vena cava resection for adrenocortical carcino- ma. Surg Today. 2007;37:291-297.
16. Cuevas C, Raske M, Bush WH, et al. Imaging primary and secondary tumor thrombus of the inferior vena cava: multi-detector computed tomography and magnetic reso- nance imaging. Curr Probl Diagn Radiol. 2006;35:90-101.
17. Ilias I, Sahdev A, Reznek RH, Grossman AB, Pacak K. The optimal imaging of adrenal tumours: a comparison of different methods. Endocr Relat Cancer. 2007;14:587-599.
18. Bower TC, Nagorney DM, Cherry KJ Jr, et al. Replacement of the inferior vena cava for malignancy: an update. J Vasc Surg. 2000;31:270-281.
19. Illuminati G, Calio’ FG, D’Urso A, Giacobbi D, Papaspyropoulos V, Ceccanei G. Prosthetic replacement of the infrahepatic inferior vena cava for leiomyosarcoma [with discussion]. Arch Surg. 2006;141:919-924.
20. Del Campo C, Konok GP. Use of a pericardial xenograft patch in repair of resected retrohepatic vena cava. Can J Surg. 1994;37:59-61.
21. Hemming AW, Reed AI, Langham MR Jr, Fujita S, Howard RJ. Combined resection of the liver and inferior vena cava for hepatic malignancy [with discussion]. Ann Surg. 2004;239:712-721.
22. Nardo B, Ercolani G, Montalti R, et al. Hepatic resection for primary or secondary malignancies with involvement of the inferior vena cava: is this operation safe or haz- ardous? J Am Coll Surg. 2005;201:671-679.
23. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007;356:2372-2380.