Clinical Review
Recommendation for standardized surgical management of primary adrenocortical carcinoma
Sébastien Gaujoux, MD, PHD,a,b,c and Murray F. Brennan, MD,d Paris, France, and New York, NY
Background. Operative resection is the only potentially curative treatment for primary adrenocortical carcinoma (ACC), but standards of operative care are not defined with regards to the extent of local resection. We propose recommendations for operative management.
Methods. Anatomic and clinical literature review focusing on local management of ACC, including lymphadenectomy and resection of adjacent organs or large vessels.
Results. First-order drainage nodes of the adrenal gland include the renal hilum lymph nodes, the celiac lymph nodes, and the para-aortic and paracaval lymph nodes, mainly above the renal pedicle and ipsilateral to the adrenal glands. Lymph node involvement occurs in about 20% of patients with ACC, and is an important prognostic factor, but lymphadenectomy is performed infrequently. The adrenal glands and kidneys are contained in the same anatomic space, but systematic en bloc nephrectomy has no proven benefits for survival. Direct invasion of the kidney or adjacent organs is rare, but major venous invasion with tumor thrombus is relatively common. Both are associated with decreased survival, but complete resection can lead to long-term survival.
Conclusion. Standardization of regional lymphadenectomy including first-order drainage nodes is proposed. Systematic nephrectomy is not necessary in the absence of gross local invasion, but locally involved organs or large veins should be resected en bloc, with tumor thrombus embolectomy, if R0 resection is possible. Operative standardization improves tumor staging, potentially decreases local recurrence, and may be associated with better survival. Evidence-based standards of operative care and prospective investigations within international collaborating groups are necessary. (Surgery 2012;152:123-32.)
From the Department of Digestive and Endocrine Surgery,“ Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris; Ecole de Chirurgie, Assistance Publique Hôpitaux de Paris (AP-HP), Paris; INSERM U1016, CNRS UMR8104, Institut Cochin, Endocrinology, Metabolism and Cancer Department, Paris, France; and the Department of Surgery,a Memorial Sloan-Kettering Cancer Center, New York, NY
ADRENOCORTICAL CARCINOMA (ACC) is a rare and aggressive endocrine neoplasm with a worldwide incidence of approximately 1 per million,1,2 acc- ounting for 0.2% of cancer-related deaths in the United States.3 Adjuvant treatment (chemotherapy and/or radiotherapy) is of limited effectiveness,
Supported by a grant from the European Society of Surgical On- cology (Dr Gaujoux).
Accepted for publication September 22, 2011.
Reprint requests: Sébastien Gaujoux, MD, PHD, Department of Digestive and Endocrine Surgery, Cochin Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), 27 rue du Faubourg Saint Jacques, Paris, France 75014. E-mail: sebastien.gaujoux@gmail. com.
0039-6060/$ - see front matter @ 2012 Mosby, Inc. All rights reserved.
doi:10.1016/j.surg.2011.09.030
and to date operative resection is the only poten- tially curative option. Recurrences, both local and metastatic, are reported in up to 85% of patients af- ter resection,4,5 and overall the prognosis remains poor, with a 5-year survival rate of 16% to 47%.1,6-8
The most powerful prognostic factor for ACC remains the completeness of initial operative resection,4,9-11 but standards of operative care are not defined, and no recommendations are avail- able from national or international societies. Improvement in operative management, particu- larly with regard to the necessity and extent of local resection, could decrease the high local recurrence rate12,13 and contribute to increasing overall survival. Regional lymph node involvement has a negative association with overall survival,14 but remains accessible to curative resection, as
recently reported by Fassnacht et al15 in a proposal for a revised 2004 International Union Against Can- cer (UICC) staging classification, validated in North America16 on Surveillance, Epidemiology and End Results (SEER) registries. Lymphadenectomy contributes to better staging, and an adequate lym- phadenectomy based on adrenal lymphatic anat- omy appears advisable. The need for systematic nephrectomy is controversial. The adrenal glands and kidneys are contained in the same small ana- tomic space (ie, the perirenal space enclosed by the anterior and posterior renal fasciae or Gerota’s fascia). Almost 20 years ago, Icard et al17,18 advo- cated that nephrectomy would help to decrease the high recurrence rate of ACC, because it would allow wide operative margins and avoid violating the tumor anatomic space, but this opinion has not yet been validated by clinical studies. The in- volvement of adjacent organs, renal vein, or inferior vena cava (IVC) is frequent in ACC, and represents a poor prognostic feature. The feasibility and effi- cacy of complete resection for ACC extending into these organs is questionable but can be associ- ated with prolonged survival.
This study, based on reviews of both anatomic and clinical literature, addresses the lymphatic anatomy of the adrenal gland, the importance of lymphadenectomy associated with curative resec- tion of ACC, the necessity of nephrectomy, and resection of involved adjacent organs, or large vessels. We propose recommendations for the operative treatment of patients with primary ACC.
METHODS
The MEDLINE database was searched via the PubMed interface selecting articles published through December 2010. Relevant English or French language studies conducted on human sub- jects were reviewed, including studies on cadavers. Additional textbooks, theses, and communications from the French Anatomical Society, found at the French National Library of Medicine (Bib- liothèque Interuniversitaire de Medecine et d’odon- tologie [BIUM], Paris, France) or in the library of the Paris Institute of Anatomy were also included.
RESULTS
Extent of lymphadenectomy in ACC. Anatomic review. Reliable data concerning the anatomy of the adrenal lymphatic drainage is limited. The first anatomic description of lymphatic drainage is attributed to Mascagni19 and Cruikshank20 at the end of the 18th century. The anatomic basis of ad- renal lymphatic anatomy, however, is derived
mainly from the publications of Sappey21 (1874; Fig 1), Gregoire,22 and Rouvière.23 Despite the technical difficulties of lymphatic mapping, most of the studies are concordant in their description of the main adrenal lymphatic stream. Lymph col- lecting vessels are found originating from the adre- nal cortex and spaced evenly within the adrenal capsule.24-30 The presence of lymphatic collecting vessels within the adrenal medulla remains contro- versial. On rare occasions, lymph nodes in contact with the adrenal gland interrupt some of the lymph-collecting vessels and appear to be the first tier of drainage. 21,22,27
Collecting vessels have been described as anterior and posterior by Gregoire22 and others.22,23,27,31 The posterior lymphatic drainage flows to lymph nodes located: posterior to the IVC, and on the right edge of the aorta for the right adrenal gland, or on its right left edge for the left gland, stretching from the celiac region near the di- aphragmatic crus to the renal vessels. The anterior lymphatic drainage flows downward to the lumbo- aortic nodes and ends in the interaorticocaval space, on the right edge of the aorta for the right ad- renal gland, and on its right left edge for the left gland and mainly around the renal hilum. Collect- ing nodes can be located below the renal pedicle, sometimes extending as far as the origin of the iliac vessel.27 Most authors concur in describing a lym- phatic drainage that passes through the diaphragm directly into the posterior mediastinal nodes.2 According to Merklin,24 who studied 68 adult post- mortem specimens, a majority of lymphatic chan- nels run medially to the thoracic duct, often without the involvement of any lymph nodes. This anatomic description is controversial, and was not observed by Hidden and Caplan27 in 47 dissections.
Description of the different pathways appears not to be relevant clinically. It is impossible to predict which pathway would be involved in case of a malignant lesion, because all pathways would probably be involved simultaneously because of the size, often >10 cm, of ACC at diagnosis, and considering that the lymphatic stream can be disorganized because of the tumor volume or lymph node involvement. It is relevant to focus on the main collecting lymph nodes representing the first tiers in the lymphatic drainage of the adrenal gland (ie, the celiac, para-aortic, and paracaval lymph nodes, including the renal pedi- cle). These observations are confirmed by an in vivo study using activated carbon particles injected under the capsule of adrenal neuroblas- toma in children.32 In this study, authors suggest that primary regional nodes are the nodes at the
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Fig . IX.
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origin of the renal artery, while the secondary re- gional nodes are para-caval and para-aortic. Involvement of the lymph nodes at the origin of the celiac trunk and the superior mesenteric artery was noted in more advanced neoplasms, in which the usual lymphatic route was obstructed by cancer invasion. It is important to note that lymphatic drainage of the adrenal glands is independent. Indeed, no lymphatic vessels cross the median axis represented by the aorta in any anatomic stud- ies. Consequently, the lymph nodes draining the right and left adrenal gland remain on the right and left side of the aorta, respectively. Rouvière23 stated that lymph from the upper pole of the right adrenal gland may enter the liver, but others have not confirmed this observation. A schematic illus- tration of abdominal lymphatic nodes collecting lymph from the right and left adrenal glands is represented in Fig 2.
From a practical point of view, the first-order drainage nodes of the adrenal gland seems to be the celiac lymph nodes, the renal hilum lymph nodes, and the para-aortic, paracaval lymph nodes originating from the aortic hiatus close to the point of origin of the celiac artery to the renal pedicle and ipsilateral to the tumor. These obser- vations are in accordance with node involvement observed in other adrenal neoplasms such as neuroblastoma. 33
Clinical review: The most powerful prognostic factor in ACC remains the quality and complete- ness of the initial operative resection.4,9-11 This concept was highlighted at MD Anderson Cancer Center,34 where overall survival was significantly better for patients submitted to operation in this high-volume center compared with those referred after primary resection. Supporting data comes
from the Memorial Sloan Kettering Cancer Center (MSKCC),9 where patients undergoing a complete primary resection had a median survival of 74 months (5-year survival, 55%), whereas patients undergoing an incomplete primary resection had a median survival of 12 months (5-year survival, 5%; P <. 001). Nevertheless, the surgical manage- ment and prognosis of ACC has not appreciably evolved over time,14 and standards of operative care, especially regarding lymphadenectomy, have not been defined by any surgery associations, soci- eties, or networks. The lack of operative standard- ization makes complete pathologic staging difficult, as reported in a MSKCC study,35 where
lymph node specimens were sampled in 39% of patients, or in the French Endocrine Society (AFCE) multicentric study,11 where lymphad- enectomy was performed in only one-third of the patients without any explanation regarding the reasons for such an approach. This multi- institutional study highlights the heterogeneity of operative management of ACC and consequently a need for standardization, with particular atten- tion to lymphadenectomy. The variable prevalence of lymph node involvement reported in the litera- ture17,36,37 may represent individual or institu- tional bias to perform regional lymphadenectomy.
The lack of standardization of lymphadenec- tomy in ACC may explain the absence of differ- ence in survival regarding stage II and III reported in various studies,34,38 the discrepancy reported regarding lymph node involvement ranging from 4% to 73%,39,40 and the high rate of local recur- rence, especially lymph node recurrence.12,13 Lymph node involvement in large series from the literature is difficult to assess, because the involve- ment is rarely reported specifically, and neither the Sullivan et al41 nor Lee et al42 classifications specify lymph node status. The recent analysis of ACC from the SEER database of the National Cancer Institute2 does not give any information regarding the clinical importance of lymph node involvement or lymphadenectomy. A previous report on 29 postmortem examinations suggests frequent involvement of lymph nodes in ACC, approaching 73% of patients.40 In 3982 patients identified from the National Cancer Data Base (NCDB)14 who were operated on in the United States from 1985 to 2005, pathologic nodal status was reported in 17.6% (n = 716), and 26.6% of these patients (n = 190) had nodal metastasis. In the German ACC registry,15 of 416 patients, the rate of lymph node involvement in ACC was 15%. Nevertheless, no data were available with regard to the type of lymphadenectomy performed (or not) or the lymph node ratio or localization of involved lymph nodes.
In these articles,14,15 overall survival was signifi- cantly worse in patients with positive lymph nodes. The NCDB14 reported significantly better 5-year survival in patients with negative nodes versus pa- tients with positive nodes (41.8% vs 13.6%; P < .0001). In the German ACC registry,15 the clinical outcome of patients with a positive lymph node was significantly worse than the outcome of pa- tients without positive lymph nodes (hazard ratio, 2.5; 95% confidence interval, 1.2-5.7). Neverthe- less, these patients still remain accessible to cura- tive treatment, with a 10-year overall survival up
to 40% for patients with stage III tumor and posi- tive lymph nodes, and without venous tumor thro- mbosis, tissue infiltration, or invasion of adjacent organs.15 Because the prognosis of such patients remains better than for those with stage IV disease (distant metastasis), substantial modification of the UICC (Union Internationale Contre le Can- cer)/World Health Organization (WHO) 2004 tumor-node-metastasis (TNM) classification has been proposed by the European Network for the Study of Adrenal Tumors (ENSAT) group, classify- ing all node positive patients without distant metastasis as stage III, regardless of primary characteristics of the neoplasm.15 This approach highlights the prognostic relevance of lymph node involvement and the need for adequate lym- phadenectomy, at least for adequate staging.
Local or locoregional recurrence appears fre- quently and is the most common site of recurrence in some series-up to 65%.12,43 Fassnacht et al12 reported, in a small case-matched study in the absence of adjuvant radiotherapy, a 40% local recur- rence rate in patients within the first year and 70% at 2 years, and overall a 60% local recurrence within 5 years after complete tumor resection in the German ACC registry. Patterns of local recurrence have been assessed recently,13 suggesting a high rate of local lymph node involvement around the aorta, vena cava, and renal hilum, without involvement contra- lateral to the tumor. The authors recommended ad- juvant radiotherapy to cover the tumor bed and the lymphatic drainage of the adrenal gland in patients at high risk for local recurrence (eg, incomplete/R1 resection).13 This high rate of early lymph node re- currence suggests an inadequate initial lymphade- nectomy for most patients, and favors a systematic, extended initial lymphadenectomy, planned preop- eratively, and not based on node gross appearance. To our opinion, lymphadenectomy should include the celiac, renal hilum, para-aortic, and/or para- caval lymph nodes ipsilateral to the tumor, starting close to the aortic hiatus and going down around the renal vessels.
Regarding the potential early involvement of posterior mediastinal nodes, to date no clinical data are available to confirm the anatomic descrip- tion of a direct stream to those nodes. While we are not able to prove that lymphadenectomy can improve disease-free survival (DFS) and overall survival (OS), because of the lack of available data, it is interesting to note than in the only study reporting lymphadenectomy for ACC,11 a trend toward a increased 5-year survival was observed when lymphadenectomy was performed (42% 5-year survival vs 36%; P = . 06).
Need of nephrectomy or adjacent organ resec- tion in ACC. Anatomic review: The adrenal gland and the kidney both originate from the intermediate mesoderm. The adrenal gland develops adjacent to the kidney, and both are included in the same anatomic space (ie, the perirenal space limited by the anterior and poste- rior renal fasciae or Gerota’s fascia, the dense, collagenous, elastic connective tissue sheath that encompasses the kidney, the adrenal gland, and the surrounding fat28). There is no complete fascial layer between the adrenal gland and the kid- ney, but rather only a thin perforate septum.44 Usu- ally, the anterior and posterior layers of Gerota’s fascia are described as fixed firmly to each other above the adrenal glands,45 enclosing the adrenal and upper poles of the kidneys. Whether this ana- tomic space is really closed by the fusion of the layers remain controversial. Other recent studies described the superior aspect of the perirenal space as open 46-50 on the bare area of the liver and the retrohepatic portion of the IVC on the right and on the subphrenic, extraperitoneal space on the left; indeed, these observations have been con- firmed by clinical observation and computed to- mography.47-50 This anatomic detail could explain the direct liver involvement sometime observed in right ACC or the involvement of the spleen and pancreas in left-sided ACC. The existence of a non- closed perirenal space would make nephrectomy useless in a case of extraadrenal tumor spread, because it is likely that the tumor would have spread also to other extraperitoneal spaces.
Clinical review. Little is known regarding the need for systematic, en bloc nephrectomy for ACC. Because of the close anatomic presence of lymph nodes with renal hilum, a more radical lymphadenectomy with removal of retroperito- neal fat and monobloc nephrectomy has been advocated by some to decrease local recur- rence.17,18 In the Italian National Registry for Ad- renal Cortical Carcinoma, this hypothesis was not corroborated,10 and there was not any improve- ment in DFS and OS in patients undergoing ne- phrectomy. Because of the lack of evidence, nephrectomy should be performed only if re- quired by local invasion or if adequate extended regional lymphadenectomy cannot be performed without nephrectomy. These results should be in- terpreted with caution because of the small sam- ple size, without stratification on MacFarlane stages.
In the multicentric experience of the French Association of Endocrine Surgeon (AFCE) Study Group,11,17 nephrectomy was performed in 20% to
30% of patients, without explanation for such an approach. In univariate analysis, no benefit from extended resection11 or from nephrectomy was observed17 (71% of the kidneys removed were not invaded by tumor). In the multicentric Italian study,10 nephrectomies were performed in 16% of patients, but no statistical difference in DFS was observed between groups. The reason for nephrec- tomy was not detailed, and nephrectomy was not stratified by tumor stage, making these results dif- ficult to interpret.
In clear cell renal carcinoma, adrenal removal was considered previously to be mandatory because of possible involvement either through local extension, lymphatic spread, arterial embolization, or retro- grade venous embolization. Nevertheless, ipsilateral adrenal involvement is noted in only 2% to 5% of specimens, mainly in large, upper pole neoplasms or in the case of renal vein thrombosis, and is suspected most of the time on preoperative imaging. Overall, adrenalectomy at nephrectomy has not been shown to afford an overall survival advantage, and an increasing number of authors51,52 recommend that adrenalectomy should not be performed rou- tinely during nephrectomy.
Direct invasion of the kidney by ACC is rare,53 even in cases with renal vein involvement, but data on this phenomenon are scarce. In our experience, this invasion should be suspected on preoperative imaging and justifies, if not present, a renal-sparing resection whenever possible, but including lymphadenectomy of the renal hilum and removal of all the surrounding fat up to the upper pole of the kidney. The new ENSAT classifi- cation has clarified the prognostic importance of tumor extending beyond the adrenal gland (ie, stage III ACC). Neoplasms that infiltrate surround- ing tissue or invade adjacent organs have a similar prognosis and should be considered as T3 and T4, stage III neoplasms in the absence of distant metas- tasis. These patients have a 30% to 40% 5-year survival rate.15 These observations support an aggressive operative approach with en bloc, multi- organ resection when complete resection can be accomplished. To our opinion, this is only justi- fied when adjacent organs appear radiologically or macroscopicaly invaded.53
Renal vein and inferior vena cava invasion in ACC. Anatomic review: The adrenal venous system is much simpler than the arterial one. Usually a single main vein exits the hilum of the adrenal gland.28,55 The IVC embryology, with the development, regression, and anastomosis of the embryonic veins, explains the asymmetry between the left and the right adrenal veins. On
the left side, the adrenal vein is long, about 15 to 35 mm, with a normal diameter of 3 to 8 mm and emp- ties directly into the left renal vein at its superior edge 20 to 40 mm from the entry of the left renal vein into the IVC. On the right side, the adrenal vein is shorter, about 6 mm long, with a normal di- ameter of 3 to 6 mm, and empties directly into the IVC in its retrohepatic portion on the posterior right side about 40 mm above the emptying of the right renal vein into the IVC. These anatomic con- siderations are important for vascular control of pheochromocytoma or ACC with venous involve- ment. In addition, on both sides, but predomi- nantly on the left,28 many accessory adrenal veins run adjacent to the arteries and empty into the phrenic or renal vein or the azygos system.
Clinical review: ACC with extension to the adre- nal, renal vein, or IVC has been noted to be as frequent as 25% in the Cochin and MSKCC series54,56 and was more frequent on the right side because of the shorter length of the adrenal vein. This condition can be a life-threatening complication because of the risk of pulmonary tumor embolism and is associated with a poorer OS and DFS.15,56
Best assessed by Doppler ultrasonography, trans- esophageal echocardiography, and magnetic reso- nance imaging, vascular extension is usually an endoluminal tumor thrombus without invasion or attachment to the venous wall but with possible retrograde extension. Thrombectomy can be performed with venous control achieved by IVC cross-clamping, hepatic vascular exclusion, or cardiopulmonary bypass, according to the level of the thrombus; the cavotomy is then closed56 by direct suture. Even if ligation of the IVC is neces- sary because of IVC occlusion, it is rare for this disease to require IVC replacement, because renal outflow is preserved by the development of collat- eral drainage.54 In order to achieve a negative vas- cular margin, the adrenal vein on the right must be ligated flush with the IVC, but when the tumor is contained in the adrenal veins, a vascular cuff of the IVC must be taken. On the left side, the adre- nal vein is ligated as it enters the left renal veins. If the adrenal vein contains tumor, then the kidney may need to be resected; however, if the gonadal vein and the azygos system are patent, the left renal vein can be resected as it passes behind or in front of the aorta, but the kidney can be preserved.57 Of- ten the tumor thrombus extends to margin of the aorta, but not into the IVC from a left-sided lesion, especially if the renal vein passes behind the aorta.
According to the ENSAT classification,15 a tumor thrombus in the vena cava or in the renal
vein is considered a T4, stage III neoplasm, in the absence of distant metastasis. Nevertheless, the long-term prognosis of these patients seems worse than that of patients with stage III disease with only infiltration of the surrounding tissue or invasion of adjacent organs. Overall prognosis remains poor, as shown by several studies: no long-term survival in the German cohort,15 a lack of follow-up in the rare available series,54,58,59 and only a very few long-term survivors, reported mainly as clinical cases.58,60,61 The recent MSKCC experience56 contrasts with these disappointing results with a 29% 3-year survival rate in 35 pa- tients with large vessel involvement (renal vein or IVC). In renal cell carcinoma, in which renal and IVC involvement is frequent (up to 10%), vas- cular involvement is classified as T3 a, b, or c ac- cording to the cephalad extent of the thrombus; extension beyond the renal vein carries a worse prognosis.62 Nevertheless, these patients may achieve long-term-survival when complete resec- tion is possible.
Overall, vascular resection should be attempted if R0 resection is expected, but the potential for long-term survival should be balanced with the potential for high postoperative morbidity and mortality, especially in patients with suprahepatic IVC involvement. The advent of hypothermic cardiopulmonary arrest with cerebral perfusion has decreased mortality, but substantial morbidity persists.
DISCUSSION
In patients with ACC, even when resectable at presentation, as many as 75% to 85% relapse, with up to 65% recurring locally.12,43 Therapeutic management of ACC has not changed substantially over the past 20 years,14 with lymphadenectomy performed only in one-third of patients in multi- institutional studies.11 This lack of standardization suggests that oncologic principles and standards of operative care for adrenal malignancy are neces- sary, especially as to the extent of lymphadenec- tomy, the need for nephrectomy, and resection of other locally involved organs or vessels. Herein, we propose a standardized approach of local management of ACC, based on the available anatomic and clinical data.
According to our anatomic and clinical review, lymphadenectomy should be part of the standard of care, because it would improve staging and may impact DFS and OS. The therapeutic benefit of lymph node clearance in ACC remains to be proven, but worldwide, there is a consensus on the improvement of oncologic results by adequate
lymphadenectomy. In rectal cancer, total mes- orectal excision (TME) has been claimed to virtually eliminate all locally recurrent disease after “curative” resection. Although this proce- dure adds to operative time and complications,63 TME is now the standard of care. In colon cancer, adequate lymphadenectomy correlates with im- proved survival, independently of stage, patient demographics, or tumor characteristics,64,65 and an increased number of negative lymph nodes66 or lymph node ratio67 has been established as a prognostic factor. Meticulous lymphadenectomy encompassing the whole field of tumor spread may improve cure rates of ACC and decrease the variability of outcomes between surgeons and in- stitutions. According to anatomic studies, lym- phadenectomy should include the celiac, renal hilum, and latero-aortic lymph nodes of the supra- renal aorta ipsilateral to the tumor. The minimum number of lymph nodes needed to detect lymph node invasion after adrenalectomy in patients with ACC remains to be determined. The clinical value of extensive lymphadenectomy to the celiac lymph nodes in addition to removal of the pri- mary lesion in curable ACC is questionable, be- cause its involvement is considered a contraindication to resection in a large variety of cancers, such as liver,68 gastric,69 or pancreatic cancers.70 Nevertheless, because of the proximity of the adrenal glands to the celiac axis, celiac lymph nodes could be considered as one of the first regional lymphatic tiers. These nodes should not be considered equivalent to distant metastasis, and consequently patients with such a disease ex- tent remain candidates for potentially curative re- section. The potential benefit of such extended lymphadenectomy should be balanced by the sub- sequent morbidity, because most studies regarding extended lymphadenectomy in upper mesocolic cancer, such as pancreatic7 or gastric cancer,72 failed to prove any benefit to survival. Lymphade- nectomy may aid in providing better staging and selection of patients with a high likelihood of recurrence.73,74 who might benefit from multi- modal adjuvant treatment strategy, including mito- tane, chemotherapy, and/or radiotherapy. This approach is under investigation for patients with a low/moderate risk of relapse (ADIUVO [a ran- domized trial on adjuvant mitotane treatment in patients with adrenocortical carcinoma at low- intermediate risk of progression who underwent radical resection]).75 But, as with other condi- tions, such as gastric cancer, the use of radioche- motherapy to substitute for inadequate resection should be discouraged.
At this time, routine nephrectomy to improve local or node clearance cannot be recommended in the absence of local involvement. It is not supported by clinical evidence and may limit the use of adjuvant or palliative chemotherapy because of nephrotoxicity to the remaining kidney. Ana- tomic studies reveal that the rostral aspect of the perirenal space might be open, and in this case, it is likely that involvement of the perirenal fat might be associated with spread to another retroperito- neal compartment that would render useless the removal of only the perirenal space. Moreover, postoperative renal insufficiency could hinder the use of mitotane as an adjuvant treatment or the use of chemotherapy in case of unresectable recurrent or metastatic disease. Local extension to adjacent organs such as the kidney, liver, or pancreas, or the large vessels (the IVC and/or renal vein), this possibility should be suspected based on preoperative cross-sectional imaging, should lead to en bloc resection. Nevertheless, these patients are at high risk of recurrence and the individual risk/benefit balance should be discussed.
The operative management of ACC remains controversial with regard to the best operative approach for localized disease, with conflicting results from available studies.76-81 It is likely-as shown for various other cancers82-that if the ex- act same resection is performed by laparoscopy or laparotomy, similar results are expected. In our opinion, a laparoscopic approach for ACC should be avoided, at least until such time as a clear standard of operative care has been achieved and established for the open approach.83 Patients followed prospectively by specialized centers have improved survival,84 and it is likely that pa- tients with ACC benefit from undergoing opera- tion in high volume centers, as shown for other cancers. 85
Standardization and quality control of resection appears to be essential for the evaluation and comparison of various treatments in retrospective and prospective studies. In a previous large multicenter study38 on the benefit of mitotane as an adjuvant treatment, tumor stage did not appear to have significant prognostic value. Be- cause no standardization of operative staging or operative quality of care occurred in the 56 centers involved, it is expected that staging was imprecise at best. Overall, better results are crucial for the more selective use of adjuvant therapy in the future, and technique and extent of operative re- section should be taken into account in future prospective trials.
We would like to thank Geneviève Hidden and Cécile Muller for helpful discussions and collaboration and Terry Helms for the drawing.
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