ORIGINAL ARTICLE - ENDOCRINE TUMORS
Resection of Adrenocortical Carcinoma Liver Metastasis: Is it Justified?
Sébastien Gaujoux, MD1, Hikmat Al-Ahmadie, MD2, Peter J. Allen, MD1, Mithat Gonen, PhD3, Jinru Shia, MD2, Michael D’Angelica, MD1, Ronald Dematteo, MD1, Yuman Fong, MD1, Leslie Blumgart, MD1, and William R. Jarnagin, MD1
1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Biostatistics and Epidemiology, Memorial Sloan- Kettering Cancer Center, New York, NY
ABSTRACT
Background. Adrenocortical carcinoma (ACC) liver metastases (LM) represent a therapeutic challenge, and it is unclear whether resection is justified. This study assesses long-term outcome and prognostic factors after liver resection for metastatic ACC.
Methods. Patients who underwent resection of ACC LM were identified from institutional databases. Recurrence, survival, and tumor characteristics, including ß-catenin and TP53 status based on immunohistochemistry and sequencing, were reviewed. The prognostic value of vari- ables was assessed with log-rank test for univariate analysis and Cox proportional hazard models for multivariate analysis.
Results. From 1978 to 2009, 28 patients (20 females; median age, 45 years), including 11 with synchronous metastasis and 3 with extrahepatic metastasis, underwent resection for ACC LM (major hepatectomy in 61%). Postoperative mortality was nil and morbidity 55%. On pathological examination, tumors were multiple in 68%, with a median size of 43 mm, and resections were R0, 1, and 2 in 59%, 33%, and 7%, respectively. All 28 patients developed recurrent disease, which was treated surgically in 11, including repeat hepatectomy in 4. Of the 15 patients
with adequate tissue for analysis, ß-catenin immunostain- ing was positive in 7, with 4 corresponding CTNNB1 mutations associated with decreased survival; p53 staining was positive in 5 (4 with corresponding TP53 mutations). The median disease-free and overall survival after hepa- tectomy was 7 and 31.5 months, respectively, with a 5-year survival of 39%. In multivariate analysis, nonfunctional tumor and surgical treatment of recurrence were indepen- dent predictors of good outcome.
Conclusions. In selected patients with ACC LM, resection is associated with long-term survival and is, therefore, justified but rarely curative.
Adrenocortical carcinoma (ACC) is a rare and aggres- sive endocrine neoplasm with a worldwide incidence of approximately 0.5 to 2 per million population.1 Surgery remains the only curative option for these patients, but overall the prognosis remains poor with a 5-year survival rate of approximately 40%.2,3 Metastatic disease is a common feature, with approximately one-third of patients presenting with synchronous metastasis.2,4 More than half will develop distant metastases despite apparent complete initial resection of the primary tumor; the liver is one of the most frequently involved organs.3,5 Because adjuvant treatment, including the adrenolytic drug mitotane (o,p’DDD), chemotherapy, and radiotherapy are of limited effectiveness, 5-year survival rate for patients with meta- static disease is less than 20%, with a median survival between 6 and 20 months.6,7 Increased survival has been observed with resection and repeated resection of adreno- cortical carcinoma,8,9 but to date there are few data available on long-term outcome after liver resection for metastatic ACC, and prognostic factors remain ill-defined.
Electronic supplementary material The online version of this article (doi: 10.1245/s10434-012-2358-7) contains supplementary material, which is available to authorized users.
@ Society of Surgical Oncology 2012
First Received: 5 September 2011; Published Online: 21 April 2012
W. R. Jarnagin, MD e-mail: jarnagiw@mskcc.org
Considerable advances toward understanding the molecular mechanisms of adrenocortical carcinoma development have been made recently.1º Importance of the activation of the Wnt/B-catenin pathway in adrenal cortex tumorigenesis, in part through ß-catenin gene (CTNNB1) mutation, is now well documented.11 Moreover, it has been recently suggested that Wnt/ß-catenin pathway activation might lead to more aggressive tumors and could be used as prognostic factors in resected primary ACC.11,12 In the same manner, P53, a protein that regulates the cell cycle in response to DNA damage, has been implicated in adreno- cortical tumorigenesis. Loss of heterozygosity in 17q13, locus where P53 tumor-suppressor gene (TP53) is located, has been reported in approximately 80% of ACC, and inactivating mutation in the TP53 tumor-suppressor gene in up to 30% is associated with a poor-outcome, as in other cancers. 12-15
This study was undertaken to assess the long-term out- come of patients after liver resection of metastatic ACC and the potential involvement of Wnt/B-catenin and TP53 pathways, as assessed by immunohistochemistry and direct sequencing, in tumorigenesis and prognosis.
MATERIALS AND METHODS
Patients and Tissue Collection
Between 1978 and 2009, patients who underwent hepatic resection for ACC metastases (European Network for the Study of Adrenal Tumors classification (ENSAT) stage IV) were identified by review of the Memorial Sloan- Kettering Cancer Center institutional and liver resection databases.2 Patients who underwent right hepatic resection for direct tumor extension of a right adrenocortical carci- noma (ENSAT stage III) were excluded. Surgery was indicated when R0 resection was considered possible on preoperative workup and/or when hormonal symptoms were not controllable with medical therapy. Extrahepatic metastases were not considered a contraindication if they were resectable or otherwise treatable. Preoperative workup included endocrine studies to assess for glucocor- ticoid secretion and imaging studies to assess the disease extent. The presentation of hepatic metastases was con- sidered synchronous when diagnosed within 6 months of primary tumor treatment and metachronous when the hepatic disease-free interval was greater than 6 months. The magnitude of hepatectomy was classified as major (≥3 hepatic segments) or minor (<3 hepatic segments), according to Couinaud’s classification. Demographic and radiologic data were obtained from retrospective medical record review. For each patient, diagnosis was confirmed by pathological examination of tumor tissue removed
during surgery. Staging of the lesion was performed using the ENSAT classification validated on Surveillance, Epi- demiology and End Results (SEER) registries in North America.2,16 Tumor analysis and access to clinical data was approved by our institutional review board.
Pathological Examination and Immunohistochemical Staining
For diagnosis and scoring, the tumors were fixed in formalin, embedded in paraffin, and 4-um sections were cut and stained with hematoxylin and eosin. Immunohis- tochemistry for ß-catenin, Ki-67, and TP53 was performed as previously described.11,14,17 Nuclear staining was quantitatively assessed, taking into account the most positive part of the stained section. Nuclear staining greater than 1% was recorded as abnormal ß-catenin accumulation, and nuclear staining greater than 5% was recorded as abnormal P53 accumulation as previously reported for adrenocortical carcinoma.11,14 Mitotic count was recorded as the number of mitotic figures per 50 high-power fields (HPF).
Genomic DNA Isolation, PCR Amplification and Sequencing, and Mutation Detection
Genomic DNA isolation, polymerase chain reaction (PCR) amplification and sequencing, and mutation detec- tion are detailed in Supplemental Data 1. Briefly, genomic DNA was extracted from frozen specimens or formalin- fixed, paraffin-embedded tissue using commercially avail- able kits. The exonic regions of interest, exon 3 of CTNNB1 gene and the whole TP53 gene (NCBI Human Genome Build 36.1), were broken into amplicons of 350 bp or less, and specific primers were designed to cover the exonic regions plus at least 50 bp of intronic sequences on both sides of intron-exon junctions. PCR reactions were carried using a touchdown PCR protocol. Templates were purified using AMPure (Beckman Coulter Genomics, Beverly, MA) and sequenced bidirectionally. Mutations were detected by using an automated detection pipeline at the MSKCC Bioinformatics Core. All putative mutations were confirmed by a second PCR and sequencing reaction.
Statistical Analysis
Values were expressed as median (interquartile) or percentage, as appropriate. Fisher exact test was used to compare differences in discrete or categorical variables, and the Wilcoxon rank-sum test was used for continuous variables. Disease-free survival (DFS; time from surgery to time of clinical evidence of local, regional, or distant relapse, or death due to any cause) and overall survival
(time from surgery for metastatic disease until death, regardless of cause) were estimated by the method of Kaplan-Meier, and the log-rank test was used to compare survival curves. Patients were censored as of their last follow-up visit if they were alive and/or disease-free throughout the study period. Variables with a P < 0.1 in univariate analysis were entered into a Cox proportional hazard model, excluding pathological and mutational data because of too few observations. The number of events in the data did not allow for a full multivariate analysis, fol- lowing the general principle of at least ten events per variable.18 Instead, we used best subset selection with the leaps and bounds method, choosing the model with the highest likelihood out of all models with two variables. 19 All tests were two-sided. For all tests, statistical signifi- cance was defined by P < 0.05. Data were analyzed with the STATA 11 statistical software (StataCorp. 2009. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP).
RESULTS
Population and Tumors Characteristics
Between 1977 and 2009, 28 patients (20 females (71%) and 8 males (29%)) underwent hepatic resection for adre- nocortical (ACC) liver metastases (LM). Regarding patients and tumors characteristic (Supplemental Data 2), median age at liver surgery was 45 years (range, 36-63). All patients underwent resection of their primary tumors, including 11 (39%) with associated liver resection for synchronous metastasis. The primary tumor was located on the right in 12 cases (43%), bilateral in 1, and was a functional tumor in 15 (54%). Primary tumors were clas- sified as stage I in 1 case (4%), II in 4 (14%), III in 12 (43%), and IV in 11 (39%). Overall, 17 (61%) patients presented with metachronous liver metastasis. In these patients, the median interval time between initial surgery and resection of the liver metastasis was 27.7 months (range, 18.9-52); two had previous surgery for lung metastasis and one for a local recurrence.
Procedure and Postoperative Outcome Description
Details of operative management are summarized in Supplemental Data 2. Briefly, median operative time was 240 min (range, 210-320), and median blood loss 1000 ml (range, 300-2400). A major hepatectomy was performed in 17 patients (61%). Operative mortality was null and overall complication rate 55% (n = 12). For patients with func- tional tumors, all were clinically free of hormonal symptoms after surgery. Additionally, three patients
underwent a second hepatectomy, one had third hepatec- tomy, and seven additional patients (39%) had surgery for extrahepatic recurrence.
Pathological and Mutational Characteristics of the Tumors
Details of histologic and mutational analyses are out- lined in Table 1 and Supplemental Table 3. Pathological examination confirmed the adrenal origin of all metastases. Liver metastases were multiple in 15 cases (68%), had a median maximal tumor size of 43 mm (range, 27-80), and a bilobar distribution in 11 cases (39%). Resection was R0 (complete resection) in 16 patients (59%), R1 (micro- scopically positive margin) in 9 (33%), and R2 (macroscopically positive margin or disease in the remnant liver) in 2 (7%). Tumor tissue was available for sequencing in 15 patients and for immunohistochemistry in 17. Pro- liferation index, as measured by Ki-67, was 15% (range, 10-30%), and mitotic count (by 50 HPF) was 17 (range, 13-26). ß-catenin nuclear expression was >1% in seven patients (41%) and p53 nuclear expression >5% in seven patients (41%; Fig. 1). CTNNB1 mutations in exon 3 were found in four cases, all with ß-catenin nuclear expression >1%. TP53 mutations were found in four cases, three of which also had p53 nuclear expression >5%, including two with CTNNB1 mutations. Overall, six tumors (35%) did not show nuclear expression of ß-catenin or p53, and nine tumors (60%) had no ß-catenin or TP53 mutations detected.
| n (%)/median (IQ) | |
|---|---|
| No. of liver metastasesª | 2 (1-4) |
| Multiple metastasesª | 15 (68%) |
| Bilobar liver metastasis | 11 (39%) |
| Size of the largest metastases (cm)ª | 4.3 (2.7-8.0) |
| Pathological margina | |
| R0 | 16 (59%) |
| R1 | 9 (33%) |
| R2 | 2 (7%) |
| ß-catenin nuclear immunostaining ≥1% | 7 (41%) |
| CTNNB1 mutation | 4 (27%) |
| TP53 nuclear immunostaining ≥5% | 7 (41%) |
| TP53 mutation | 4 (27%) |
| Mitotic count (by 50 HPF) | 17 (13-26) |
| Mitotic count ≥20 (by 50 HPF) | 7 (41%) |
| Ki-67 | 15 (10-30) |
| Ki-67 ≥20% | 6 (35%) |
IQ interquartile; HPF high-power field
a Based on patients with accurate available data
A
B
C
D
E
F
G
H
I
J
K
L
Disease-free, Overall Survival, and Prognostic Factors
Accurate information on recurrence date was available for 23 patients. After hepatectomy, all patients recurred. The median disease-free survival after hepatectomy was 7 months.
Follow-up information for survival was available for all patients. After a median follow-up of 28 months (range, 12-78), the median survival after hepatectomy for ACC liver metastasis was 31.5 months. The 1-, 2-, and 5-year survival after hepatectomy was 78%, 63%, and 39%, respectively. Overall, 25 patients died during follow-up, 9
Survival
1.00
0.75
0.50
0.25
0
12
24
36
48
60
72
84
96
108
120
Time (months)
patients survived to 5 years, and 2 survived to 10 years (Fig. 2).
Univariate analysis (Table 2) showed that left-sided primary tumors, minor hepatectomy, absence of CTNNB1 mutation, absence of ß-catenin nuclear staining, and Ki-67 < 20% were associated with poor overall survival. In multivariate analysis (Table 3), excluding pathologic and mutational data because of far fewer observations, a nonsecreting tumor and surgical treatment of recurrence were independent prognosis factor of good outcome. Regarding pathologic and mutational data (Table 3), Ki-67 ≥ 20% and CTNNB1 mutations were associated with a decreased OS (P = 0.006 and 0.004, respectively), and ß-catenin nuclear immunostaining ≥1% with a trend to a decrease in OS (P = 0.06).
Disease Recurrence and Management
Recurrence and related management are summarized in Table 4. Briefly, of the 28 recurrences, 27 were initially distant sites, including 12 hepatic only, and 5 lung only recurrences. The 10 other recurrences were immediately multiple, including liver (n = 8) lung (n = 7), or bone (n = 4). Overall, 21 patients initially recurred within the liver. Treatment of recurrence was surgical in 11, including repeat hepatectomy in 4, lung resection in 6, and resection of local (adrenal) recurrence in 2. These procedures led to a R0 resection with no evidence of disease after treatment of recurrence in 8 patients.
DISCUSSION
Surgical management of noncolorectal liver metastasis is now widely accepted and in highly selected patients is associated with long-term survival.20 Nevertheless, the
| n | Median OS (mo) | Univariate analysis p | Multivariate analysis p | OR (95% CI) | ||
|---|---|---|---|---|---|---|
| Age (yr) | ||||||
| <45 | 14 | 31.5 | 0.2148 | |||
| >45 | 14 | 26.3 | ||||
| Gender | ||||||
| Female | 20 | 28.3 | 0.1167 | |||
| Male | 8 | 97.6 | ||||
| Initial ENSAT stage | ||||||
| I-II | 5 | 23.4 | 0.6107 | |||
| III-IV | 23 | 31.5 | ||||
| Side of the lesion | ||||||
| Right | 12 | 73 | 0.0072 | 0.821 | 0.4-1.9 | |
| Left | 15 | 26.3 | ||||
| Secreting tumors | ||||||
| No | 13 | 73 | 0.0960 | 0.015 | 1.2-7.3 | |
| Yes | 15 | 23.4 | ||||
| Synchronous liver metastasis | ||||||
| No | 17 | 28.3 | 0.7089 | |||
| Yes | 11 | 33.9 | ||||
| Bilobar liver metastases | ||||||
| No | 17 | 41.8 | 0.1661 | |||
| Yes | 11 | 28.3 | ||||
| Extrahepatic metastasis at/ | ||||||
| prior | ||||||
| hepatectomy | ||||||
| No | 25 | 31.5 | 0.7717 | |||
| Yes | 3 | 28.3 | ||||
| Major hepatectomy (yes) | ||||||
| No | 11 | 18 | 0.0286 | 0.433 | 0.3-1.8 | |
| Yes | 17 | 67.3 | ||||
| Redo hepatectomy | 0.1095 | |||||
| (yes) | ||||||
| No | 24 | 28.3 | ||||
| Yes | 4 | 103.5 | ||||
| Surgical treatment of recurrence (yes) | ||||||
| No | 17 | 18 | 0.0033 | 0.001 | 2-18 | |
| Yes | 11 | 71.3 | ||||
| Maximum size >43 mmª | ||||||
| No | 11 | 33.9 | 0.2723 | |||
| Yes | 11 | 26.3 | ||||
| Multiples metastasisª | ||||||
| No | 10 | 12.6 | 0.4370 | |||
| Yes | 12 | 31.5 | ||||
| Pathological margina | ||||||
| R0 | 16 | 31.5 | 0.2650 | |||
| R1 | 9 | 23.4 | ||||
| R2 | 2 | 97.6 | ||||
a Patients with available data
| n | Median OS (mo) | Univariate analysis P | |
|---|---|---|---|
| ß-catenin nuclear immunostaining ≥1% | |||
| No | 10 | 33.9 | 0.06 |
| Yes | 7 | 28.3 | |
| CTNNB1 mutations | |||
| No | 11 | 33.9 | 0.004 |
| Yes | 4 | 6.2 | |
| TP53 nuclear immunostaining ≥5% | |||
| No | 10 | 31.5 | 0.86 |
| Yes | 7 | 67.3 | |
| TP53 mutation | |||
| No | 11 | 33.9 | 0.17 |
| Yes | 4 | 13.3 | |
| Mitotic count ≥20% | |||
| No | 10 | 67.3 | 0.31 |
| Yes | 7 | 13.3 | |
| Ki-67 ≥20% | |||
| No | 11 | 41.8 | 0.006 |
| Yes | 6 | 11.5 | |
Based on patients with available data
| Site of initial recurrence | n |
|---|---|
| Local (adrenalectomy site) recurrence only | 1 |
| Distant recurrence | 27 |
| Hepatic only | 12 |
| Hepatic and local (adrenalectomy site) recurrence only | 1 |
| Lung only | 5 |
| Immediately multiple distant site recurrences including | 10 |
| Liver | 8 |
| Lung | 7 |
| Bone | 4 |
| Others | 4 |
| Treatment of recurrence | n |
| Surgical treatment | 11 |
| Repeat hepatectomy | 4 |
| Lung resection | 6 |
| Resection of local recurrence | 2 |
| R0 after surgical treatment of recurrence | 8 |
outcome depends on patient selection and the primary tumor, and little is known regarding such an approach in ACC. In this series of 28 patients, we show that in selected patients an aggressive surgical approach to ACC liver metastasis is associated with long-term survival, but rarely
to cure, with a median overall survival of 31.5 months and 5-year survival of 39%.
Management options for patients with metastasis from ACC are limited and reported outcomes have been poor. Overall, the 5-year survival is below 15-20% with a median survival less than 20 months.2,6,7,21,22 Available chemotherapy has limited efficiency and includes the his- toric and widely used adrenolytic agent mitotane, with a doubtful effect on survival.23,24 Other chemotherapy regi- mens have response rates of approximately 25%, and a clear definition of the first-line therapy awaits the results of the FIRM-ACT study.25-27 Radiofrequency ablation has been advocated by some for the treatment of stage IV ACC, but evidence for improvement in local control or improved survival is lacking.28-32 Another promising alternative for the treatment of liver metastatic ACC is the use of transarterial chemoembolization as advocated by Baudin et al. in the Gustave Roussy Institute (IGR) expe- rience, reporting a median survival of 11 months in patients with progressive disease.33 Overall, it is likely that these different approaches may have a role in selected cases in a multidisciplinary management approach; how- ever, surgery, when complete resection is possible, should be strongly considered for the management of patients with resectable recurrent disease.
Review of the English literature reveals limited experi- ence specifically related to the surgical management of ACC liver metastasis, and the current study represents the largest reported series. Indeed, studies regarding ACC liver metastasis have mainly been published as clinical case reports, mixed with liver metastasis from multiple primary sites.34,35 The recently published NIH (National Institute of Health) series, including 19 resected adrenocortical liver metastasis, showed that liver resection for metastatic adrenocortical carcinoma could be performed safely and with potential benefit in highly selected cases, although the overall 5-year survival was poor at 29%, and recurrence was nearly universal.32 As reported for other liver meta- static tumors, and in accordance with recommendations of an international consensus conference on the management of patients with adrenal cancer, the current study suggests that an aggressive surgical approach in selected patients with liver metastasis can lead to long-term survival; how- ever, it is important to note that 5-year survival does not translate to cure.36 Indeed, none of the patients in this series survived without recurrence.
Although none of the patients in the present study were cured after hepatic resection, this was associated, in a subset of patients, with improved overall survival com- pared with historical controls. Therefore, prognostic factors are needed for better patient selection and to tailor man- agement. The only independent prognostic factor available preoperatively found in this study was the presence of a
nonsecreting tumor, as previously reported by others.5,37 Other reported prognostic factors, such as disease free- interval <12 months, the presence of extrahepatic disease, and R2 resection, were not significantly associated with improved survival.20 This can be explained partially by the limited size of the cohort and a highly stringent preopera- tive selection of these 28 patients. Indeed, our practice has been to select carefully patients based on both operative risk and biological behavior/tumor aggressiveness of the disease. In our opinion, classically used prognostic factors, such as tumor burden (number, size of metastasis and presence of extrametastatic localization), tumor presenta- tion (synchronous vs. metachronous with long disease-free interval), biologic characteristic of the primary tumor (node-positive, Weiss score, Ki-67, and mitotic index), and possibility to perform radical resection (R0/R1 vs. R2) should be considered on a case-by-case basis in the risk- benefit balance of patients with ACC liver metastasis. As always in retrospective studies, a causal association can only be suggested, and whether a favorable biological behavior of some tumors or the treatment is responsible for the observed results is difficult to assess. In their recent report, Ripley et al. also examined clinical prognostic factors, including synchronous/metachronous presentation, neoadjuvant and adjuvant therapy, number of hepatic lesions, presence of extrahepatic disease, resection status after surgery, and disease-free interval.32 Overall, only a disease-free interval greater than 9 months after primary adrenalectomy was associated with longer survival. This led them to conclude that the biology of ACC itself may be the major determinant of outcome, underscoring the need for a more accurate surrogate, such as histological or molecular, described in the present experience.
The radicality of resection (R0 vs. R1 vs. R2) was not a prognostic factor in this study. This may be the result of a lack of power due to a small sample size, but perhaps also related to the benefit of debulking surgery in a subgroup of patients. Indeed, debulking surgery (resection of more than 80-90% of the tumor) is sometimes considered for patients with large, symptomatic tumors (because of the low like- lihood of tumor shrinking by chemotherapy) or for patients with secretion uncontrolled by usual medical therapy. In these two groups of patients, it is possible that surgery could improve both survival and quality of life. In addition, surgical treatment of recurrence was noted as an indepen- dent prognosis factor of good outcome, but this might only be a surrogate for small-volume recurrent disease.8,38,3 Response to preoperative chemotherapy has been shown to be an important prognostic factor in the surgical treatment of liver metastasis from a variety of primary sites, and some have suggested that mitotane could be used in the neoadjuvant setting to select patients for surgery.40 42 The very high rate of early recurrence is a strong rationale for
chemotherapy treatment in patients with ACC hepatic metastases, either adjuvant or neoadjuvant, but is limited by lack of effective agents and no evidence of bene- fit.32,43,44 Because cytotoxic chemotherapy has shown disappointing results, targeted therapy represents a poten- tially important alternative approach, and specifically agents targeting the Wnt/B-catenin pathway.45-47 Indeed, the results of the present study showed that CTNNB1 mutations are associated with a worse outcome following resection of ACC hepatic metastases, confirming other reports, but this only applies to a third of patients. 11,48,49 Additionally, the presence of ß-catenin nuclear immuno- staining was significantly associated with the presence of a Ki-67 > 20% (P=0.035); the latter also is an adverse prognostic factor (P = 0.006). Regarding TP53 activation, its prognostic role is more controversial and was not observed in this series. 14,50 These results, however, should be interpreted with some caution due to the small sample size. Overall, whether hepatectomy should be performed if pejorative predictive factors, such has Ki-67 > 20%, or CTNNB1 mutations are present remains to be determined.
As mentioned, one of the pitfalls of this study is the relatively small number of patients treated over a long period of time. However, the rarity of the disease and the fact that most patients with metastatic disease are not candidates for resection make it difficult to study a larger cohort. These facts underscore the need to organize an effective surgical collaborative working group to conduct meaningful studies. Indeed, for such a rare disease, ran- domized trials are very unlikely to occur soon, and we strongly believe that progress in a near future will only come from national or international collaborative studies, such as that currently organized in Europe within the ENSAT group.
CONCLUSIONS
Resection of ACC liver metastasis is associated with long-term survival in selected patients, with a median overall survival of 31.5 months and a 5 year-survival of 39%. However, cure is generally not achievable. The use of neoadjuvant or adjuvant chemotherapy, particularly agents targeting the Wnt/B-catenin pathway, may ultimately improve the results of surgical therapy but is not yet a clinical reality.
ACKNOWLEDGMENT The authors thank Igor Dolgalev and Adriana Heguy from the Geoffrey Beene Translational Oncology Core at Memorial Sloan Kettering Cancer Center for their help in sequencing, and all the surgical and pathology department staff for their precious collaboration.
DISCLOSURES Sébastien Gaujoux was recipient of a grant from the European Society of Surgical Oncology (ESSO), and the
Association Française de Chirurgie Hépato-Biliaire et de Transplan- tation Hépatique (ACHBT).
CONFLICT OF INTEREST There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
FUNDING This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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