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European Journal of Surgical Oncology
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EJSO ONCOLOGY SURGICAL ONLINE
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A standardized surgical approach to multifocal locoregionally recurrent left-sided adrenocortical carcinoma
Shruthi R. Peratia, Alyssa V. Eade a, Aaron Dinermana, Katherine M. Barrows ª, , Rachael Lowney ªD, Lindsay R. FriedmanaD, Tracey Puª, Carolina Larrain aD, Leila Sarvestania, Ashley Rainey a, Cathleen Hannah a, Tamika Magee b, Andrew M. Blakely a D, , Jeremy L. DavisaD, Naris N. Nilubolª, Jaydira del Riverob, Jonathan M. Hernandez ª,
a Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA b Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
ARTICLE INFO
Keywords:
Locoregional recurrence Adrenocortical carcinoma (ACC) en bloc multi-visceral resection
ABSTRACT
Introduction: Society guidelines recommend surgery for recurrent adrenocortical carcinoma (ACC) in selected patients; however, no standards exist to guide surgeons, and this may be particularly problematic in the man- agement of multifocal locoregional recurrence.
Materials and methods: A standardized approach was developed for patients with multifocal locoregionally recurrent left-sided ACC as part of an NCI study (NCT05237934). En bloc resection included the distal pancreas, spleen, left kidney, portion of left diaphragm, and possibly a portion of the left lateral liver, greater curve of the stomach, and/or descending colon. Morbidity, survival, and quality of life (QoL) were assessed.
Results: From 2018 to 2024, ten patients (median age 59 years) underwent multi-visceral en bloc resections for multifocal locoregionally recurrent left-sided ACC. Prior to surgery, 90 % of patients had undergone systemic therapy and a median of one prior operation (range 1-4). Size of local recurrence(s) averaged 6.5 cm (range 1.9-12.2 cm) at largest diameter, with a median of 3 (range 2-8) foci of disease identifiable on pre-operative imaging. Two patients (20 %) developed a Grade 1B post-operative pancreatic fistula. There were no peri- operative mortalities. Median locoregional recurrence-free survival was 22.1 months at 19.3 months of me- dian follow-up. 50 % of QoL survey respondents reported feeling recovered/back to baseline activity level within 4 months of surgery.
Conclusion: Locoregional control can be obtained with reasonable success and acceptable morbidity in select patients with multifocal locoregionally recurrent left-sided ACC using a standardized left upper quadrant en bloc multi-visceral resection approach. Verification of the results of this technique is required in other experienced centers.
1. Introduction
Adrenocortical carcinoma (ACC) is a rare disease, with a reported incidence of 1.02 per million, and represents less than 1 % of adrenal tumors encountered in clinical practice [1]. Histologically, these tumors are composed of sheets of tumor cells without much stroma, rendering manipulation problematic for risk of compromise to tumor integrity, rupture, intra-abdominal seeding, and locoregional recurrence [2]. Accordingly, recurrence rates have been reported to be as high as 64-85 % following curative-intent resection of the primary tumor [3,4]. The
risk of locoregional recurrence has been associated with left-sided ACC in particular, which is slightly more common (51.6-53.7 %) than right-sided ACC [1,4]. The diagnosis of recurrent adrenocortical carci- noma portends a poor prognosis and its management is complex, owing to limited efficacious options beyond first-line systemic therapy [5].
While surgical resection is the cornerstone of management for pri- mary ACC, its role in the management of disease recurrence is complex due to challenges of the re-operative, often radiated, field and multifocal nature of disease [5,6]. Currently, society guidelines recommend sur- gery for recurrent ACC only in select situations in which complete
* Corresponding author.
E-mail address: jonathan.hernandez@nih.gov (J.M. Hernandez).
https://doi.org/10.1016/j.ejso.2025.110395
resection can be achieved and with a disease-free interval (DFI) greater than 12 months, although details regarding standards for this re-do approach are lacking [7]. Several studies on repeat resections report associations between various parameters (R0, Ki-67 %, sex, etc.) and survival, but the retrospective nature of the studies and the lack of surgical detail make it impossible to know which patients to select and difficult to know what operations specifically to select them for (tumor enucleation with minimal margins, limited visceral resections, renal/spleen-preserving resections, resections combined with HIPEC, multi-visceral en bloc resections) [8,9].
We posit that recurrence may not solely reflect disease biology but rather may also reflect the conduct of preceding operation(s), necessi- tating an aggressive en bloc approach to a “contaminated” field. While patient selection is best suited for multi-disciplinary team discussions, there is a need to delineate a standard surgical approach for patients with multifocal locoregionally recurrent left-sided ACC, or the ambi- guity surgeons face regarding the procedural management of this patient population will persist. Given our hypothesis that locoregional control in a re-operative field with multifocal disease is best achieved through a left upper quadrant (LUQ) en bloc approach, we developed a standard- ized technique and evaluated outcomes in a small cohort of patients, including locoregional control, morbidity, and quality of life (QoL).
2. Materials and Methods
2.1. Patient cohort
All patients were enrolled in a single-institution prospective (ongoing) natural history study (NCT05237934) from May 2018 to November 2024, approved by the NIH Institutional Review Board. This is an interim analysis exploring a tertiary aim of the overall study. All patients provided informed written consent. Each patient’s case was discussed at a multi-disciplinary endocrine tumor board prior to offering surgical intervention. We emphasize that patient selection (with multi- disciplinary consensus) for operative intervention is paramount. The decision for en bloc resection was multifactorial but was generally predicated upon more than one focus of disease on pre-operative im- aging, consistent with a “contaminated” field. Details of prior operation (s) such as tumor rupture, as well as time from the initial operation, were considered. Patients with isolated recurrence years into the disease course were managed in an organ-sparing manner depending upon location, whereas those with multifocal disease were generally more appropriate for multi-visceral en bloc resection as is presented here. Additionally, history of radiotherapy was considered, as prior radiation can compromise tissue planes and make en bloc resection necessary to avoid inadvertent compromise to tumor integrity.
Pre-operative work-up includes contrast-enhanced CT of the chest/ abdomen/pelvis, FDG PET scan [10,11], and nuclear medicine reno- gram (which calculates the percentage of renal filtration for each kid- ney) to assess contribution from each kidney with additional nephrology and/or urology consultation recommended [12]. Pre-operative imaging often revealed the need for partial gastrectomy and/or descending colectomy. The critical planes that determine resectability with negative margins are along the aorta, proximal SMA, and the celiac axis.
2.2. Technique: left upper quadrant en bloc resection approach
The principle guiding the employment of this en bloc multi-visceral resection is the perception of a contaminated field with more than one lesion identifiable on pre-operative imaging. As these tumors tend to fracture with direct manipulation, this technique allows the surgeon to avoid directly handling the tumor/immediately adjacent tissue. This is a reproducible technique than can be modified as needed.
1. Diagnostic Laparoscopy
2. An upper midline incision in made from the xiphoid to umbilicus and may be extended lower depending upon a given patient’s anatomy.
3. A Bookwalter retractor is preferred. The initial retractor positions are as follows:
a. Short body wall on segment 2/3 of the liver
b. Long body wall on the gallbladder
c. Left and right-sided body wall retractors with initially more pull right
4. Reflect the omentum from the transverse colon. The omentum can be divided longitudinally at any point along its length to leave any “suspicious” portions with left-sided structures.
5. Mobilize the distal portions of the ascending colon and hepatic flexure to enable a full kocherization of the duodenum.
6. Divide the left renal vein at its junction with the vena cava.
7. Identify the superior mesenteric vein and dissect the anterior portion of this vein cephalad to make a tunnel underneath the pancreas neck.
8. Divide the pancreas at the neck.
9. Divide the splenic vein at its junction with the superior mesen- teric vein.
10. Divide the splenic artery at its origin from the celiac axis.
11. Remove the Bookwalter retractor on liver segment 2/3 and divide the triangular and coronary ligaments until the suprahepatic vena cava/left hepatic vein is identified and retract the entire liver (except spigelian lobe of caudate) to the right of the vena cava using a malleable retractor.
12. Completely divide the gastrosplenic ligament including short gastric vessels to the EG junction. Of note, if this plane has been violated or is “tumor adjacent”, portions of the greater curve of the stomach can be divided to remain with the left-sided mass. The stomach should now be retractable to the right of midline.
13. Incise the ligament of Treitz to allow retraction of all small bowel to the right of midline.
14. The Bookwalter retractor is now adjusted as follows:
a. Malleable on liver and stomach to retract these organs to pa- tient right.
b. Large malleable(s) to retract the small bowel to patient right.
c. Two small left-sided body wall retractors (one cephalad and the other caudad) to fully expose the left hemiabdomen.
15. The distal transverse colon and descending colon with mesentery are fully assessed. There are three choices for dealing with this anatomy, which may (and often does) form the proverbial roof of the en bloc resection.
a. Colon and mesentery are uninvolved: fully mobilize trans- verse, descending and sigmoid colon with mesentery and adjust small bowel retractor such that now it includes all bowel to the right of aorta.
b. Colon is uninvolved but a portion of the mesentery is tumor- adjacent: Incise the mesentery preserving the marginal ar- tery laterally. Decide on medial extent required for mesenteric resection and fully divide the mesentery leaving it attached to the en bloc mass. Fully mobilize the colon (with its large mesenteric defect) to patient right as above. Of note, there will be plenty of time for colonic ischemia to declare itself if this is a concern.
c. Colon and mesentery are involved or tumor adjacent: Divide the distal transverse colon and descending colon/sigmoid colon junction. Divide the colon mesentery medially in a plane parallel with the aorta, preserving the main IMA and its branches to the sigmoid colon. Retract the distal transverse colon and sigmoid colon to the right of the aorta.
16. Identify the left iliac artery. This is the most caudal aspect of the dissection. Do not divide the left gonadal vessels (or ureter) at this time, as this is the major venous outflow for the mass/left kidney given prior ligation of the left renal vein.
17. Dissect along the left iliac artery until its origin with the aorta and carry the dissection cephalad skeletonizing the aorta <180° on the left. Preserve the IMA. Nodal tissue posterior to the aorta should be swept left. Divide the left renal artery when encoun- tered. The left renal vein staple line should be swept to the left. Preserve the SMA and celiac axis with the surrounding nerve tissue.
18. Divide the remining tissue between the aorta (posteriorly) and the stapled end of the pancreas to allow the mass to be completely detached medially from the aorta. At this point, the aorta should be visualized along its entire abdominal length.
19. Divide the left gonadal vein and ureter as they cross over the left iliac artery and incise the fascia overlying the psoas and quad- ratus lumborum muscles superiorly. The dissection is carried out until the inferior insertion of the diaphragm is encountered.
20. The diaphragm is the incised superiorly, as caudal as is onco- logically acceptable starting close to the spleen and then carried medially and laterally. Care is taken not to injure lung paren- chyma. Anterolateral retraction from the thorax facilitates medial division of the diaphragm. This region is often in close proximity to tumor and care must be taken to avoid encountering tumor directly.
21. The diaphragm insertion posteriorly is the remaining connection to the abdominal cavity is now divided and the mass carefully removed from the abdomen.
22. A small chest tube is left in the left thorax and the diaphragm is repaired primarily or with mesh as the situation dictates.
23. Bowel anastomoses are performed.
24. 19Fr Blake drains are placed in the left upper quadrant and along the cut edge of the pancreas.
A detailed description of the post-left upper quadrantectomy en bloc resection bed (capturing the skeletonized aorta with transected renal artery, splenic artery, splenic vein, and pancreatic neck) is depicted in the supplemental video.
2.3. Data collection and analysis
Data on patient demographics, surgical characteristics, locoregional disease-free survival (DFS), and overall survival (OS) were assessed. To assess health-related QoL, a voluntary survey including questions from the 30-item European Organisation for Research and Treatment of Cancer survey questionnaire (EORTC QLC-C30 version 3.0, measuring QoL in cancer patients) was sent to all living patients in August 2024 with voluntary responses collected up until October 2024 [13-15]. Further details on the EORTC QLC-C30 version 3.0 questionnaire are as follows: it includes five functional scales (physical, role, cognitive, emotional, and social functioning), a global QoL scale, three symptom scales (fatigue, nausea and vomiting, and pain), and six single-item measures (appetite loss, diarrhea, dyspnea, constipation, insomnia, and financial difficulties). The questionnaire covers a 1-week period and primarily uses a four-point response format (“not at all,” “a little,” “quite a bit,” and “very much”), except for the global QoL scale, which employs a seven-point response format. Scores were linearly transformed to a 0-100 scale, where higher scores indicate better health for the func- tioning and global QoL scales, but greater symptom burden for the symptom scales [16]. Based upon the methods introduced from Saina et al., QoL impairment was categorized as normal, mild, moderate, and severe [17]. For the global health status and functional scale, the QoL impairment is denoted as normal (76-100), mild (51-75), moderate (26-50) and severe (0-25). As the symptom scale has a reverse order of scoring, the QoL impairment is denoted as normal (0-25), mild (26-50), moderate (51-75) and severe (76-100). Basic statistical calculations were performed on Excel, and Kaplan-Meier Curves were produced using GraphPad.
3. Results
3.1. Cohort demographics
Ten patients underwent LUQ en bloc resections for multifocal locoregionally recurrent left-sided ACC. These patients are referenced as, “Patient 1,” through, “Patient 10,” in order of earliest to most recent date of surgery. Of these patients, 3 (30.0 %) were male, and 7 (70.0 %) were non-Hispanic white (Table 1). The mean age of patients at the time of LUQ en bloc resection for recurrence was 56.5 years (median 59, range 22-71). Six patients (60.0 %) had an estimated time from index surgery to initial recurrence of one year or more. Patients had undergone a median of one prior operation (range 1-4) before undergoing the en bloc resection. 90 % of patients had received chemotherapy prior to LUQ en bloc resection. Four patients (40.0 %) additionally received radiation therapy, and one patient received immunotherapy prior to LUQ en bloc resection. Of note, the single patient that did not receive systemic therapy underwent an urgent operation for massive gastrointestinal hemorrhage secondary to tumor erosion (6 x 8cm) through the posterior gastric wall. Size of local recurrence(s) on pre-operative imaging aver- aged 6.5 cm (range 1.9-12.2 cm) at largest diameter, with patients having a median of 3 (range 2-8) foci of locoregional disease recurrence on pre-operative imaging.
3.2. Surgical characteristics
Given prior operative interventions, the LUQ en bloc resections included distal pancreatectomy (n = 9), splenectomy (n = 7), left ne- phrectomy (n = 8), partial diaphragm resection (n = 9), partial hepa- tectomy (n = 4), partial gastrectomy (n = 6), and descending colectomy (n = 4) (Table 2).
Six of the nine patients (66.6 %) of patients who underwent dia- phragm resection required synthetic Gore-Tex mesh repair of the defect. All patients had R0 resections (Table 2). 60 % of patients had a Ki-67 % of 30 % or greater (at index or prior operation). A median of 4.5 (range of 0-21) lymph nodes were evaluated. One patient (Patient #8) had a positive lymph node on final pathology.
The median duration of post-operative hospitalization was 23 days
| Cohort demographics | n =10 |
|---|---|
| Sex | |
| Male, n (%) | 3 (30 %) |
| Female, n (%) | 7 (70 %) |
| Race | |
| White, non-Hispanic (%) | 7 (70 %) |
| Asian, non-Hispanic (%) | 1 (10 %) |
| White, Hispanic, n (%) | 2 (20 %) |
| Ageª, median, years (range) | 59 (22-71) |
| ECOG statusª, median (range) | 0 (0-1) |
| Time from index surgery to surgery for initial recurrence | |
| Estimated recurrence <1 year, n (%) | 4 (40 %) |
| Estimated recurrence 1+ year(s), n (%) | 6 (60 %) |
| Number of prior surgeries for left ACC and locoregional recurrence, median (range) | 1 (1-4) |
| Prior Lines of Therapyª | |
| Chemotherapy, n (%) | 9 (90 %) |
| Radiation therapy, n (%) | 4 (40 %) |
| Immunotherapy, n (%) | 1 (10 %) |
| Recurrent disease on pre-operative CT imagingª | |
| Largest diameter of tumor (cm), median (range) Number of foci of recurrent disease in the abdomen/pelvis, median (range) | 6.5 |
| (1.9-12.2) | |
| 3 (2-8) | |
| Hormone-producing recurrent tumor | |
| Yes, n (%) | 1 (10 %) |
| No, n (%) | 9 (90 %) |
a At time of en bloc resection for recurrence.
| Surgical Demographics | n =10 |
|---|---|
| Total number of organs resected per case, median (range) | 5 (2-10) |
| Operation components | |
| Distal pancreatectomy, n (%) | 90 % (9) |
| Splenectomy, n (%) | 70 % (7) |
| Left nephrectomy, n (%) | 80 % (8) |
| Partial gastrectomy, n (%) | 60 % (6) |
| Partial diaphragm resection, n (%) | 90 % (9) |
| Mesh repair of diaphragm, n (%) | 60 % (6) |
| Partial hepatectomy, n (%) | 40 % (4) |
| Partial descending colectomy, n (%) | 50 % (5) |
| Post-operative course | |
| Length of stay, days, n, median (range) | 23 (9-58) |
| Post-operative complications | |
| Clavien-Dindo Classification | |
| I, n (%) | 4 (40 %) |
| II, n (%) | 3 (30 %) |
| III, n (%) | 2 (20 %) |
| IV, n (%) | 1 (10 %) |
| V, n (%) | 0 (0 %) |
| Post-operative pancreatic fistula rate, n (%) | 8 (80 %) |
| Grade 1A | 6 (60 %) |
| Grade 1B | 2 (20 %) |
| Other complication, n (%) | 3 (30 %) |
| 30-day re-admission rate, n (%) | 2 (20 %) |
| Serum Creatinine (Cr) labs | |
| Pre-operative Cr, median (range) | 0.7 (0.4-1.3) |
| Cr on day of discharge, median (range) | 0.9 (0.7-2.5ª) |
| Pathology | |
| R0 resection, n (%) | 10 (100 %) |
| Index/prior operation Ki-67 | |
| Less than 30 %, n (%) | 1 (10 %) |
| 30 % or greater, n (%) | 6 (60 %) |
| Unknown, n (%) | 3 (30 %) |
| Number of lymph nodes resected, median (range) | 4.5 (0-21) |
| Number of positive lymph nodes, median (range) | 0 (0-1) |
a Cr of 2.5 continued to resolve and was 0.9 by 1-month post-discharge.
(range 9-58) (Table 2). Two patients were readmitted within 30 days after surgery (10.0 %), and there were no peri-operative mortalities. All ten patients had at least one post-operative complication, but the ma- jority of complications were minor/Clavien-Dindo I-II (7 patients, 70.0 %). Two patients (20 %) developed a Grade 1B pancreatic fistula. The most severe complication (Grade IV) was the development of post- operative renal insufficiency that required several sessions of hemodi- alysis in the early post-operative period (n = 1); this patient’s creatinine continued to resolve after discharge, and her serum creatinine was 0.9 by 1-month post-discharge. Four patients underwent systemic treatment after en bloc resection. Of these, three patients received etoposide, doxorubicin and cisplatin (EDP), and one patient received pem- brolizumab. No patients developed nephrotoxicity due to post-operative systemic therapy.
3.3. Survival analyses
Median locoregional recurrence-free survival was 22.1 months on Kaplan-Meier analysis (Fig. 1A). As >50 % of the patient cohort remains alive in the study period, the Kaplan-Meier analysis of median OS was not calculated (Fig. 1B). Seven of the ten patients (70 %) are alive at a median follow-up time of 19.3 months (range 1.5-65.6 months).
3.4. Patients who developed locoregional recurrence after LUQ en bloc resection
Patient #2: 64-year-old female presented 4.5 years after an R0 resection of a pT4pNx left-sided ACC with a Ki-67 of 25 % (at prior operation). The recurrent ACC was positive for a mutation in NF2 (c.1490G > C nucleotide change). Following LUQ en bloc resection, locoregional recurrence was noted at 22.1 months of follow-up. To
Probability of Recurrence
100
Median DFS = 22.1 months
50
0
0
12
24
36
48
60
72
Time (Months)
Number at Risk
9
7
2
1
1
1
0
1B) Overall Survival
100
Probability of Survival
U
50
0
0
12
24
36
48
60
72
Time (Months)
Number at Risk
9
7
3
2
2
2
0
address this, the patient underwent a laparoscopic hand-assisted “peri- colonic” mass removal without colonic resection, after which the patient was restarted on mitotane maintenance therapy. Recurrence was further noted in the liver 58.9 months following LUQ en bloc resection, which was managed by percutaneous ablation. Further liver recurrences were noted 61.8 months following LUQ en bloc resection, and the patient was restarted on cytotoxic chemotherapy.
Patient #5: 60-year-old female presented 8.5 months after an R0 resection of a pT2pNx left-sided ACC, with a Ki-67 of 30 %. The recur- rent ACC was positive for TERT mutation (c .- 124C > T nucleotide change) and loss of both CDKN2A and CDKN2B. Following LUQ en bloc resection, the patient developed an abdominal wall recurrence 8.7 months later at the site of a prior percutaneous biopsy. The abdominal wall recurrence was managed with extra-peritoneal abdominal wall resection with mesh reconstruction. 19.3 months after the LUQ en bloc resection, the patient developed locoregional recurrence in the surgical bed, which is being managed with resumption of cytotoxic chemotherapy.
Patient #7: 68-year-old female presented 11.0 months after a R1 resection of a stage IV pT3pNx left-sided ACC, with a Ki-67 of 80 %. The
recurrent tumor was positive for TP53 mutation (c994-1G > T nucleo- tide change). The recurrent tumor was also testosterone-producing, based on pre-operative testing. (Following en bloc resection, the pa- tient’s testosterone level was 404 ng/dl as compared to >1300 ng/dl pre-op.) 4.6 months following LUQ en bloc resection, the patient devel- oped bone metastases (for which radiation therapy was administered), and the patient went on to enroll on a clinical trial 9.9 months after en bloc resection for progressive lung metastases. The patient ultimately developed recurrent multifocal disease in the left hemiabdomen at 13.8 months following LUQ en bloc resection.
Patient #8: 22-year-old male who presented 10.1 months following an R1 resection (tumor rupture) of a Stage III T3NxM0 primary left-sided ACC, with a Ki-67 of 45 %. The recurrent tumor was positive for TP53 (pathogenic c.857A > T (p.Glu286Val) mutation) associated with Li- Fraumeni syndrome, and PTPRD (likely pathogenic) mutations, as well as RB1 loss. 3.9 months following LUQ en bloc resection, the patient was diagnosed with rapidly progressive disease with near complete hepatic parenchymal replacement, large bilateral hilar pulmonary metastases, and a small focus of left-sided abdominal recurrence in the area of prior en bloc resection. The patient died of disease 4.4 months following LUQ en bloc resection.
3.5. Quality of life assessment
QoL survey respondents (n = 6) reported a mild impairment in global health status, mean of 62.5 (range 41.7-83.3) (Table 3). With regards to global health status, 83.3 % of respondents rated their overall health during the past week as a 4 out of 7 (1 = very poor, 7 = excellent), and 83.3 % of respondents rated their overall QoL during the past week as a 5 or higher. Respondents also reported a mild impairment in functional scales, mean 67.8 (range 50.0-80.0) (Table 3). On a four-point scale, 16.7 % of respondents reported “very much” when asked about diffi- culties with strenuous activities and long walks. When asked about less strenuous daily activities (short walk, using the toilet, limitations at work, limitations with hobbies or leisure activities), 0 %-33.3 % responded with “quite a bit”. Respondents on average had no impair- ment on the symptoms scales, mean 24.7 (range17.7-43.3) (Table 3). The majority of respondents (n = 4-6, 66.6 %-100 %) reported, “not at all,” or, “a little,” when asked about emotional impact (such as feeling depressed, irritable, worried or tense, having difficulty concentrating or remembering things). Half of respondents reported that their physical condition or medical treatment interfered with their social activities. Half of survey respondents reported feeling recovered and back to baseline activity level within 4 months of the LUQ en bloc resection (Fig. 2), and all respondents reported that they would choose to undergo the operation again if they could go back.
4. Discussion
Operative standards in oncologic surgery are important metrics that help to improve the quality of an operation at-scale, but also to communicate clearly amongst multi-disciplinary providers in down- stream cancer care [18,19]. While some procedures are difficult to standardize across diverse patient populations (e.g. partial hepatec- tomy), others lend themselves to quality metrics (e.g. colon resection,
| Global Health Status | Functional Scales | Symptom Scales | |
|---|---|---|---|
| Patient 1 | 83.3 | 77.8 | 15.3 |
| Patient 2 | 41.7 | 50.0 | 23.1 |
| Patient 3 | 66.7 | 73.3 | 25.6 |
| Patient 5 | 58.3 | 50.0 | 43.3 |
| Patient 6 | 58.3 | 75.7 | 23.1 |
| Patient 7 | 66.7 | 80.0 | 17.7 |
| Mean (n=6) | 62.5 | 67.8 | 24.7 |
pancreatectomy, adrenalectomy). For example, ACC protocol docu- mentation ensures that key components (critical to the oncologic quality of the operation and to the potential cure of ACC) are performed [20, 21]. Re-do surgery is perhaps the least well defined in so far as patient selection, and operative standards in this setting are non-existent despite being advocated for in select patients [7]. As part of an ongoing study for patients with rare tumors including ACC, we developed and imple- mented a standard technique for patients with multifocal locoregionally recurrent disease. Although the LUQ en bloc approach is aggressive, we demonstrate acceptable morbidity and QoL impact with reasonable regional disease control.
Surgical resection is the only potentially definitive treatment for ACC [5,6]. Although complete surgical resection in the recurrent setting is associated with an OS benefit, incomplete (i.e. non-R0) resection has been associated with an OS benefit when compared to non-surgical treatments [22]. Moreover, multimodal management of recurrent ACC has also demonstrated prolonged cancer-specific survival in a small cohort of patients without distant metastases and who responded well to chemotherapy and radiation therapy [23]. In other words, select pa- tients with metastatic or locoregionally recurrent disease appear to benefit from disease control even if unlikely to be cured. We feel strongly that patient selection is best decided by a multi-disciplinary disease management team, which should take into account a multitude of potentially prognostic factors [8,9,24]. One study identified patients with recurrent ACC (mixed locoregional and distant metastases) from a national cohort (across 13 institutions participating in the United States Adrenocortical Carcinoma Study Group from 1997 to 2024) and found that presence of at least two of the following factors was associated with potential OS benefit: locoregional-only or pulmonary metastases, DFI of more than one year, and only a solitary recurrent tumor [8]. Data from the National Institutes of Health (including 22 patients with local re- currences from 1977 to 2009) similarly demonstrated that a DFI of greater than one year as a prognostic factor along with left-sided later- ality of the primary tumor [9].
The most recent society guidelines recommend resection for recur- rent disease if both the DFI is greater than 12 months and the disease is completely resectable [7]. Non-operative management is recommended if the DFI is < 6 months and disease is not resectable (except for select patients with severe hormone excess) [7]. All patients in this cohort had RO resections and left-sided primaries - both of which have been shown to favor an OS benefit [8,9,24]. While 40.0 % of patients had an esti- mated DFI of less than 1 year, the DFI was greater than 6 months for all patients. Ultimately the patients included in this study were selected, but our aim was to standardize the operation they were selected for so as to guide surgeons faced with similar patients for whom surgery is a recommended option by the disease management team. Of note, we have performed a number of en bloc resections for multifocal right-sided recurrences. However, these operations are more difficult given prox- imity to the vena cava and at times necessitate en bloc resection of the inferior vena cava below the hepatic veins, possibly with a veno-veno bypass circuit. Moreover, proximity to the duodenum, head of the pancreas, liver hilum/biliary anatomy requires intra-operative decisions that are best described as customized to the induvial patient rather than standardized as described herein for left-sided multi-focal recurrences.
Patient selection for a given intervention must take into account the cost (morbidity and impact on QoL) for that specific patient. In this study, operative morbidity in the short-term (30 days) was within generally acceptable standards (see Table 2) [20]. While a median length of stay of 23 days may appear prolonged compared to typical standards, the NIH Clinical Center generally has extended hospital stays, as patients are admitted the night before surgery and there are no financial barriers to “extra hospital days.” Moreover, the majority of these cases were undertaken during the height of the COVID pandemic and patients were frequently “rehabbed” in the hospital given concern for rehabilitation center nosocomial spread. It is notable that only two patients were readmitted within 30 days (despite all ten patients having
How long after surgery did it take for you to feel recovered and back to your baseline activity level?
6 responses
33.3%
< 2 months
16.7%
1 3-5 months
6-11 months
16.7%
12 months or longer
33.3%
at least one post-operative complication). The risk of renal toxicity with cisplatin may favor patients receiving systemic chemotherapy/EDP prior to, as opposed to following, LUQ en bloc resection [25,26]. One patient in our cohort developed an acute kidney injury necessitating renal replacement therapy during the immediate post-operative period, but no patients experienced long-term renal insufficiency as a direct result of the operation. Additionally, none of the four patients who received systemic therapy (n = 3 EDP, n = 1 pembrolizumab) after en bloc resection developed nephrotoxicity, even with a single kidney. Still, the theoretical risk of renal toxicity after nephrectomy, and timing of systemic therapy should be considered.
Discussions with individual patients within this cohort have yielded valuable insights-patients frequently exhibit reluctance to endure treatments such as EDP or mitotane without perceivable advantages. In such instances, a proactive surgical resection may prove beneficial, enabling patients to abstain from systemic therapies for a period of time while undergoing diligent post-operative surveillance. We believe it is imperative to prospectively delineate prognostic factors that can inform tailored and nuanced management strategies for this patient population, aimed not only at extending survival but also at enhancing the QoL [27]. Limitations of this study include the small cohort size and single-surgeon/single-center experience, which certainly inhibits the generalizability of the results. A larger cohort is needed to better esti- mate the risks and benefits to selected patients, and longer post-operative follow-up is needed to fully assess the true longer-term survival impact of this resection approach. Additionally, the study’s lack of a comparison group raises significant selection bias in the highly-select cohort that underwent en bloc resection. Without a control group, the authors cannot say for certain whether these outcomes would have been the same if a different approach had been taken, but rather the authors have outlined a reproducible approach to multi-focal locoregional recurrence and demonstrate outcomes that are associated with it. In terms of assessing QoL, the delayed survey administration in 2024 and the single timepoint of survey data collection make these data subject to bias of time, selective recall/memory, and survivor responses, as well as variable post-operative therapy regimens and disease states. Additionally, the lack of a comparator survey before surgery limits the interpretation of QoL impact specifically attributable to surgery vs. progression of disease vs. side effects from various additional therapies. Still, we felt that these data were important to share with surgeons and patients who may considering en bloc resection.
In conclusion, aggressive en bloc surgical resection (with utilization of the “left upper quadrantectomy” technique) achieves RO resections, with the potential for durable locoregional control at an acceptable morbidity and impact on QoL. Future verification of the results of this technique is required in other experienced centers, for more complete assessment of the morbidity and survival impact of the operation.
Disclosures
None. Supplemental Video. Resection Bed Anatomy.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the intramural program of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Govern- ment. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi. org/10.1016/j.ejso.2025.110395.
References
[1] Sharma E, Dahal S, Sharma P, Bhandari A, Gupta V, Amgai B, et al. The characteristics and trends in adrenocortical carcinoma: a United States population based study. J Clin Med Res Aug 2018;10(8):636-40. https://doi.org/10.14740/ jocmr3503w.
[2] Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev Apr 2014; 35(2):282-326. https://doi.org/10.1210/er.2013-1029.
[3] Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med Jun 7 2007;356(23):2372-80. https://doi. org/10.1056/NEJMoa063360.
[4] Amini N, Margonis GA, Kim Y, et al. Curative resection of adrenocortical carcinoma: rates and patterns of postoperative recurrence. Ann Surg Oncol Jan 2016;23(1):126-33. https://doi.org/10.1245/s10434-015-4810-y.
[5] Chukkalore D, MacDougall K, Master V, Bilen MA, Nazha B. Adrenocortical carcinomas: molecular pathogenesis, treatment options, and emerging immunotherapy and targeted therapy approaches. Oncologist Sep 6 2024;29(9): 738-46. https://doi.org/10.1093/oncolo/oyae029.
[6] Lo WM, Kariya CM, Hernandez JM. Operative management of recurrent and metastatic adrenocortical carcinoma: a systematic review. Am Surg Jan 1 2019;85 (1):23-8.
[7] Fassnacht M, Assie G, Baudin E, et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol Nov 2020;31(11):1476-90. https://doi.org/ 10.1016/j.annonc.2020.08.2099.
[8] Tran TB, Maithel SK, Pawlik TM, et al. Clinical score predicting long-term survival after repeat resection for recurrent adrenocortical carcinoma. J Am Coll Surg Dec 2016;223(6):794-803. https://doi.org/10.1016/j.jamcollsurg.2016.08.568.
S.R. Perati et al.
[9] Datrice NM, Langan RC, Ripley RT, et al. Operative management for recurrent and metastatic adrenocortical carcinoma. J Surg Oncol Jun 1 2012;105(7):709-13. https://doi.org/10.1002/jso.23015.
[10] Wrenn SM, Moore AL, Shah HJ, et al. Higher SUV(max) on FDG-PET is associated with shorter survival in adrenocortical carcinoma. Am J Surg Feb 2023;225(2): 309-14. https://doi.org/10.1016/j.amjsurg.2022.08.020.
[11] Schlotelburg W, Hartrampf PE, Kosmala A, et al. Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma. Endocrine Jun 2024; 84(3):1172-81. https://doi.org/10.1007/s12020-024-03695-6.
[12] Fuller SN, Shafiei A, Venzon DJ, et al. Tumor doubling time using CT volumetric segmentation in metastatic adrenocortical carcinoma. Curr Oncol Nov 1 2021;28 (6):4357-66. https://doi.org/10.3390/curronco128060370.
[13] EORTC QLQ-C30 (version 3). 08/19/2024, https://www.eortc.org/app/uploads /sites/2/2018/08/Specimen-QLQ-C30-English.pdf.
[14] Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC quality of life group. Eur J Cancer Sep 2000;36(14):1796-807. https://doi.org/10.1016/s0959-8049(00)00186-6.
[15] Aaronson NK, Ahmedzai S, Bergman B, et al. The european organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst Mar 3 1993;85(5): 365-76. https://doi.org/10.1093/jnci/85.5.365.
[16] Cocks K, King MT, Velikova G, Martyn St-James M, Fayers PM, Brown JM. Evidence-based guidelines for determination of sample size and interpretation of the european organisation for the research and treatment of cancer quality of life questionnaire core 30. J Clin Oncol Jan 1 2011;29(1):89-96. https://doi.org/ 10.1200/JCO.2010.28.0107.
[17] Saini J, Bakshi J, Panda NK, et al. Cut-off points to classify numeric values of quality of life into normal, mild, moderate, and severe categories: an update for EORTC-QLQ-H&N35. The Egyptian Journal of Otolaryngology 31 July 2024;40:83. https://doi.org/10.1186/s43163-024-00642-0. 2024.
[18] Katz MHG, Francescatti AB, Hunt KK, Cancer Surgery Standards Program of the American College of S. Technical standards for cancer surgery: commission on
cancer standards 5.3-5.8. Ann Surg Oncol Oct 2022;29(11):6549-58. https://doi. org/10.1245/s10434-022-11375-w.
[19] Hieken TJ, Burns WR, Francescatti AB, Morris AM, Wong SL, Cancer Surgery Standards Program of the American College of S. Technical standards for cancer surgery: improving patient care through synoptic operative reporting. Ann Surg Oncol Oct 2022;29(11):6526-33. https://doi.org/10.1245/s10434-022-11330-9.
[20] Barbara S, Miller MSH, Laird Amanda M, Nehs Matthew A, Dickson Paxton V, Dy Benzon, et al. Protocol for cancer surgery documentation: adrenal cancer. Protocols for Cancer Surgery Documentation; 2024. p. 21.
[21] Yip L, Duh QY, Wachtel H, et al. American association of endocrine surgeons guidelines for adrenalectomy: executive summary. JAMA Surg Oct 1 2022;157(10): 870-7. https://doi.org/10.1001/jamasurg.2022.3544.
[22] Zhang F, Liu Z, Feng D, et al. Reoperation for recurrent adrenocortical carcinoma: a systematic review and pooled analysis of population-based studies. Front Surg 2022;9:781406. https://doi.org/10.3389/fsurg.2022.781406.
[23] Kijima T, Fukuda S, Fukushima H, et al. The role of multimodal salvage therapy in the management of recurrent adrenocortical carcinoma. Jpn J Clin Oncol Apr 29 2023;53(5):436-42. https://doi.org/10.1093/jjco/hyac207.
[24] Calabrese A, Puglisi S, Borin C, et al. The management of postoperative disease recurrence in patients with adrenocortical carcinoma: a retrospective study in 106 patients. Eur J Endocrinol Jan 10 2023;188(1). https://doi.org/10.1093/ejendo/ lvad002.
[25] Zhang J, Ye ZW, Tew KD, Townsend DM. Cisplatin chemotherapy and renal function. Adv Cancer Res 2021;152:305-27. https://doi.org/10.1016/bs. acr.2021.03.008.
[26] Morita-Ogawa T, Sugita H, Minami H, Yamaguchi T, Hanada K. Population pharmacokinetics and renal toxicity of cisplatin in cancer patients with renal dysfunction. Cancer Chemother Pharmacol Oct 2020;86(4):559-66. https://doi. org/10.1007/s00280-020-04147-4.
[27] Ruggiero E, Tizianel I, Caccese M, et al. Advanced adrenocortical carcinoma: from symptoms control to palliative care. Cancers (Basel) Nov 29 2022;14(23). https:// doi.org/10.3390/cancers14235901.