Adrenocortical carcinoma with inferior vena cava tumor thrombus
Danuel V. Laan, MD,ª Cornelius A. Thiels, DO,a,b Amy Glasgow, MHA,b Kevin B. Wise, MD,a Geoffrey B. Thompson, MD,a Melanie L. Richards, MD,a David R. Farley, MD,a Mark J. Truty, MD,a and Travis J. Mckenzie, MD,ª Rochester, MN
Background. The safety, efficacy, and prognostic implications of resection of adrenocortical carcinoma with inferior vena cava tumor thrombus are poorly described.
Methods. A retrospective review was performed during a 30-year period on patients who underwent resection of locally advanced, nonmetastatic adrenocortical carcinoma. We compared patients with and without inferior vena cava tumor thrombus, examining perioperative characteristics, completeness of resection, mortality, and survival.
Results. We identified 65 patients who underwent resection of locally advanced (T4N0 and T4N1) adrenocortical carcinoma (28 patients with inferior vena cava tumor thrombus, 37 noninferior vena cava tumor thrombus). Rate of complete resection, adjuvant chemotherapy, and short-term postoperative morbidity was similar between groups.
Overall survival was similar at 12-months. At 24 months overall survival was less in the inferior vena cava tumor thrombus group (59% vs 30%, P = . 04). Differential survival through 60-month follow-up favored the noninferior vena cava tumor thrombus group (36% vs 0%, P = . 001). Subgroup analysis including only patients with complete resection demonstrates similar survival at 24-months but at 36-months survival favored the noninferior vena cava tumor thrombus patients (65% vs 29%, P = . 047) and this continued through 60 months (40% vs 0%, P = . 049).
Conclusion. Attempt at complete resection of adrenocortical carcinoma with inferior vena cava tumor thrombus seems justified particularly as short-term safety and survival are similar to patients without inferior vena cava tumor thrombus. However, survival beyond 36-months is limited in patients with inferior vena cava tumor thrombus. Patients being evaluated for resection in the setting of inferior vena cava tumor thrombus should be selected carefully. (Surgery 2016; )
From the Department of Surgery,” Mayo Clinic; and Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, MN
ADRENOCORTICAL CARCINOMA (ACC) is a rare and aggressive neoplasm associated with a poor prog- nosis.1,2 Ninety percent of ACCs are >6 cm in size on presentation, with 40% of patients present- ing with widely metastatic disease at the time of diagnosis.3 Adjuvant chemotherapy has limited
Support provided by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery (Thiels). The authors have no relevant financial disclosures.
Presented as an oral presentation at the American Association of Endocrine Surgeons meeting, Baltimore, MD, April 10, 2016. Accepted for publication July 12, 2016.
Reprint requests: Travis J. Mckenzie, MD, Mayo Clinic, 200 First St. Southwest, Rochester, MN 55905. E-mail: Mckenzie.Travis@ mayo.edu.
0039-6060/$ - see front matter
@ 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.surg.2016.07.040
efficacy, and operative resection remains the initial treatment for ACC when technically feasible.4
The incidence of inferior vena cava (IVC) involvement in ACC is not well defined. Further- more, the safety and efficacy of ACC resection requiring IVC tumor thrombectomy or IVC resec- tion are poorly described. We aimed to compare the safety and oncologic efficacy of resection of ACC with and without IVC-TT (tumor thrombus) among patients with stage IV locally advanced, nonmetastatic, ACC, with the hypothesis that stage IV nonmetastatic ACC with IVC-TT involvement portends worse survival compared with similar stage ACC without IVC-TT.
MATERIALS AND METHODS
After obtaining institutional review board approval, a retrospective review of a prospectively collected institutional database was performed to identify all patients with ACC that underwent
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resection from 1985-2015. Only patients with locally advanced, nonmetastatic (M0) ACC were included. Those undergoing a planned palliative operation without curative intent were excluded (n = 3). Patients were selected for inclusion in the study based on TNM staging as defined by our institutional pathologists. Patients with T4 tumors, defined as tumor of any size with invasion of adja- cent organs with or without nodal involvement (T4N0 or T4N1) were included. By definition these patients are classified American Joint Com- mittee on Cancer Seventh Edition stage IV or Eu- ropean Network for the Study of Adrenal Tumors (ENSAT) stage III.5,6 All patients underwent a pre- operative evaluation, including magnetic reso- nance imaging and/or positron emission tomography/computed tomography (CT) when indicated, to rule out metastatic disease.
Comparison was made between patients with and without IVC-TT. The primary outcome of the study was overall survival. Secondary outcomes included 30-day morbidity and mortality. Subset analysis was utilized including only patients with R0 resection. Clavien-Dindo (CD) scores were used to assess grade of postoperative complications and was calculated on a 5-point scale from the medical
record.7 Analysis was performed using x2, Fisher exact test, and Wilcoxon rank-sum test as indi- cated. Overall survival was reported using the Kaplan-Meier method of analyses.
RESULTS
We identified 65 patients that underwent cura- tive intent resection of T4N0 (n = 61) or T4N1 (n = 4) nonmetastatic ACC during a 31-year period. Among this total operative group, mean age was 51.0 ± 14.6 years and 34 (52%) patients were females. Average tumor size was 13.9 ± 5.5 cm (range, 3.1-26.0 cm). RO resection was obtained in 42 patients (65% of the total cohort). Failure to obtain R0 resection was due pri- marily to residual disease in periadrenal fat (n = 15, 65%). Recurrence occurred in 54 patients (83% of the total cohort). The median survival was 17.7 months (Fig 1).
Of these 65 patients, 28 (43%) had IVC-TT and 37 (57%) did not. Groups were similar in terms of age, sex, laterality, hormonal activity, rate of R0 resection, and percentage receiving adjuvant ther- apy (Table). Within the IVC-TT group, the classifi- cation of T4 was assigned based on adjacent organ involvement in addition to IVC-TT in 46 %
| IVC-TT n = 28 | Non-IVC-TT n = 37 | P value | |
|---|---|---|---|
| Age, mean (SD) | 52.2 (14.4) | 50.0 (14.8) | .60 |
| Male (%) | 15 (53.6) | 15 (40.5) | .30 |
| Symptoms at diagnosis (%) | 13 (46.4) | 17 (45.9) | 1.0 |
| Hormonally active (%) | 10 (35.7) | 16 (44.4) | .61 |
| Laterality | .62 | ||
| Right (%) | 14 (50.0) | 16 (43.2) | |
| Left (%) | 14 (50.0) | 21 (56.8) | |
| Completeness of resection (R0, %) | 16 (57.1) | 26 (70.3) | .31 |
| Operating time (min), median (IQR) | 321 (210, 370) | 190.5 (142.5, 282.5) | .03 |
| EBL (mL), median (IQR) | 2,750 (750, 5,000) | 500 (250, 1,250) | .06 |
| Transfusion requirement (%) | 17 (60.7) | 10 (27.0) | .01 |
| T4N0 (%) | 25 (89.3) | 36 (97.3) | .31 |
| Aortocaval nodes (T4N1, %) | 3 (10.7) | 1 (2.7) | .31 |
| Other organ involvement (%) | |||
| Liver | 6 (21.4) | 11 (29.7) | .57 |
| Kidney | 4 (14.3) | 12 (32.4) | .15 |
| Grade (high) | 7 (58.3) | 13 (76.5) | .42 |
| CD Score (%) | .56 | ||
| <3 | 12 (55.0) | 16 (64.0) | |
| >3 | 10 (45.5) | 9 (36.0) | |
| Adjuvant chemotherapy, yes (%) | 14 (50.0) | 18 (48.6) | 1.0 |
| Follow-up mo, median | 10.5 | 28.0 | .02 |
| Local recurrence (%) | 7 (25.0) | 5 (13.5) | .22 |
| Distant recurrence (%) | 14 (50.0) | 18 (48.6) | 1.0 |
| Lung recurrence (%) | 10 (35.7) | 12 (32.4) | .80 |
| Liver recurrence (%) | 7 (25.0) | 5 (13.5) | .34 |
| Re-excision (%) | 2 (7.1) | 14 (37.8) | .01 |
| Median survival | 14.8 | 40.3 | .01 |
SD, Standard deviation; R0, complete resection; IQR, Interquartile range; EBL, estimated blood loss; CD, Clavien-Dindo; IVC-TT, inferior vena cava-tumor thrombus.
(n = 13) of the cohort. The remaining 54% (n = 15) were considered T4 due to IVC-TT itself. All patients had at least an abdominal CT scan pre- operatively; however, 4 patients in the IVC-TT group and 6 patients in the non-IVC TT did not have a preoperative CT scan of the chest.
Adjuvant chemotherapy was utilized equally among both groups with recurrence (25% in IVC-TT and 27% in non-IVC-TT, P = 1.00). Mito- tane was the most common adjuvant chemo- therapy delivered in both groups (65% in the IVC-TT group and 76% in the non-IVC-TT group). Other agents used were cytotoxic agents such as doxorubicin, cisplatin, etoposide, and experi- mental compounds (18% in IVC-TT group and 11% in non-IVC-TT group). Cytotoxic agents were given in conjunction with mitotane when mi- totane was tolerated. No patient received neoadju- vant therapy in our study cohort. Patterns of recurrence are outlined in Table. Distant recur- rence was more common than local recurrence
in both groups. Reoperation for recurrence was performed in 10% (n = 3) of the IVC-TT patients and 37% (n = 14) of the non-IVC-TT patients (P= . 01).
Only 11 IVC-TT patients were assigned a path- ologic tumor grade. Of these, 6 (55%) were high grade. Of the non-IVC-TT patients with a reported tumor grade (n = 17), 13 (77%) were high grade. Only 27% (n = 8) of patients had their IVC-TT identified preoperatively on cross sectional imag- ing. Level of thrombus extension superiorly into the IVC was readily noted; however, no imaging report detailed the degree of stenosis caused by the tumor thrombus. Six patients had near total or >50% stenosis identified at the time of opera- tion. IVC-TT was quantified, intraoperatively by maximal extent of the TT with the majority being infrahepatic (n = 11, 39%), followed by retrohe- patic (n = 7, 25%), suprahepatic (n = 5, 18%), and extending into the right atrium (n = 5, 18%). Seven patients (25%) in the IVC-TT cohort
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required cardiopulmonary bypass, 5 of which had TT extending into the right atrium. One patient in the IVC-TT cohort had direct invasion of IVC requiring an interposition tube graft. An open operative approach was used in all patients. No pa- tients in the IVC-TT group had clinical or imaging evidence of pulmonary embolism pre- or postoper- atively. A single patient in the IVC-TT group was started on prophylactic anticoagulation preopera- tively to prevent clot migration or embolism.
Operative factors, tumor characteristics, and postoperative morbidity are summarized in Table. Tumor thrombus removal was associated with an increased rate of transfusion requirement intrao- peratively (60 % in IVC-TT and 25% in non-IVC- TT, P = . 04). Minor postoperative complications (CD scores of I or II) were most commonly due to need for postoperative transfusion in both groups (n = 4 in IVC-TT, n = 6 in non-IVC-TT). Ma- jor postoperative complications (CD score of III or greater) were mostly due to intra-abdominal ab- scess or fluid collections requiring interventional radiology drain placement in both groups (n = 4 in IVC-TT, n = 3 in non-IVC-TT).
The median survival for patients with IVC-TT was 14.8 months compared with 43 months for
patients without IVC-TT (P= . 002). Thirty-day mor- tality for the IVC-TT group was 7.1% (n = 2) and 5.4% (n = 2) for the non-IVC-TT group (P= 1.0). Of the 2 patients in the IVC-TT group that experi- enced 30-day perioperative mortality, one of the patients that required cardiopulmonary bypass had left ventricular heart failure and the other died after discharge of unknown causes. Ninety- day mortality for the IVC-TT group was 7.1% (n = 2) and 13.5% (n = 5) for the non-IVC-TT group (P = . 70). Overall survival was similar be- tween groups at 12-months (71.8 % vs 51.8% P = . 15). At 24-months overall survival was signifi- cantly less in the IVC-TT group (59% vs 30%, P = . 04). Differential survival through 60-month follow-up favored the non-IVC-TT group (36% vs 0% at 60-months, P= . 001, Fig 2) with no survivors in the IVC-TT group at 5-year follow-up.
A subgroup analysis of only IVC-TT patients was done to determine the effect of laterality on survival. No statistical difference in survival was noted at any time point for left-sided versus right- sided tumors (Fig 3).
Complete (R0) resection was achieved in 16 (57%) of the patients with IVC-TT and 26 (70%) of the non-IVC-TT patients. Subgroup analysis
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including only patients with R0 resection demon- strated similar survival between groups up to 36 months (Fig 4); however, at 36-months follow- up survival favored the non-IVC-TT group (65% vs 29%, P = . 047), and this continued through the 60-month follow-up period (40% vs 0%, P = . 049).
DISCUSSION
Patients with IVC-TT accounted for nearly half of the patients treated operatively for locally advanced, nonmetastatic ACC at our institution in the past 31 years. Patients with and without IVC- TT were similar in regards to demographic and tumor factors. The rate of postoperative complica- tions and perioperative mortality was similar in patients with and without IVC-TT. Decreased over- all survival in the IVC-TT group, compared with the non-IVC-TT patients, became significant at 24 months and remained so through 60-months follow-up, with no survivors in the IVC-TT group at 5 years. Similarly on subgroup analysis of only patients with R0 resection, overall survival was significantly less starting at 36-months. As such, regardless of resection status, IVC-TT seems to be
an independent prognosticator for worse overall survival.
The largest single institutional case series previ- ously seen in the literature evaluating ACC with IVC-TT by Chiche et al® described 17 patients treated with operative resection. Median survival was 8 months. Level of IVC extension and opera- tive technique were detailed in full, but no com- parison was made to patients with locally advanced ACC without IVC-TT. Similarly, a multi- institutional study of ACC with IVC-TT by Mihai et al,9 examining 38 patients, described level of IVC involvement and a median survival 18 months, but did not compare outcomes to patients without IVC-TT. The safety of IVC-TT thrombectomy is largely anecdotal in the literature with case reports abounding.10-15 We show that the operation can be performed safely and that patients requiring tu- mor thrombectomy have similar perioperative morbidity and early mortality compared with pa- tients not requiring thrombectomy.
The rarity of ACC coupled with advanced pre- sentation at diagnosis makes operative outcome studies difficult to perform. The prognostic impli- cation of tumor thrombus is therefore largely
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unknown. Libé et al16 attempted to assign prog- nosis to vascular involvement in locally advanced ACC at large by utilizing the European Network for the Study of Adrenal Tumor (ENSAT) data- base. Although they found no prognostic value in vascular involvement, it is important to note that they grouped both renal and caval involvement into a single cohort, thus limiting the prognostic value of their findings. Turbendian et al17 per- formed a comparison of patients with and without large vessel extension, also defined as involvement in renal vein or IVC, and found that large vessel extension was associated with worse survival.
By isolating patients with IVC-TT and comparing those patients to American Joint Committee on Cancer Stage IV/ENSAT stage III, nonmetastatic patients without IVC-TT, we did see a survival difference starting at 24 months and favoring the non-IVC-TT patients. Patients with IVC-TT in our cohort had a median survival of 14.8 months. In comparison, Chiche et al® observed a median sur- vival of 8 months. Interestingly, 40% of their cases had IVC-TT extending to the suprahepatic IVC, compared with 18% in our study which could potentially account for impaired survival.
Previous studies have suggested that greater grade, older age, and presence of symptoms correlate with worse survival in ACC.16,18 We found that patients with and without IVC-TT were similar in regards to these specific factors, as summarized on Table. Notably, there was no difference in per- centage of patients receiving a greater grade on final pathologic examination. However, our dataset was limited in regards to the number of patients who were actually assigned a grade on pathology (n = 28). Although this is reassuring, in that we may infer that patient’s with IVC-TT did not have greater tumor grades and thus bias our results, ul- timately the low number of patients receiving a pathologic grade hinder our conclusions. It should also be noted that a consistent pathologic grading system for ACC, like the Weiss system, was not readily utilized by out institutional pathologist.1
Icard et al20 suggested that completeness of resection is one of the key determinants of improved survival after resection of ACC. Similar to their study, we found a survival advantage for pa- tients who had R0 resection versus incomplete resection (R1, R2). Subgroup analysis including only patients with R0 resection, demonstrated
that survival significantly favored the non-IVC-TT group starting at 36 months and remained favor- able thereafter. This subgroup analysis allows us to draw conclusions on IVC-TT as an independent prognostic factor apart from the bias of complete- ness of resection.
The current ENSAT staging system does not describe IVC-TT in its TNM classifications. One might assume IVC-TT to be direct invasion of an adjacent organ (T4), but this is not clearly defined. If considered T4, IVC-TT itself apart from other organ involvement would be classified as ENSAT stage III. Based on our data, IVC-TT seems to be independently associated with worse survival when compared with ENSAT stage III patients without IVC-TT. This may justify upstaging of patients with IVC-TT from otherwise stage III classification to stage IV disease.
A study utilizing the National Cancer Database by Bilimoria et al21 showed that treatment utiliza- tion and survival in ACC has remained consistent since the 1980s. During the past decade, we have seen an increase in cytotoxic adjuvant chemo- therapy use at our institution. Mitotane was the most commonly used medication in our cohort and remains the only Food and Drug Administration-approved drug for the treatment of ACC. Subgroup analysis of patients treated with these agents was not possible in this study due our small sample size. Bednarski et al22 did show that when patients with borderline resectable ACC, defined as imaging suggesting a need for multiorgan/vascular resection, were treated with neoadjuvant cytotoxic therapies, there was no dif- ference in disease free survival or overall survival at 5 years compared with patients who had initial operation followed by chemotherapy, suggesting a benefit of neoadjuvant treatment sequencing in patients with borderline resectable ACC.
We observed a greater rate of resection of recurrent disease in the non-IVC-TT group. We hypothesize that a lesser rate of resection of recurrent disease in the IVC-TT group may be explained by their worse median survival (14 months), compared with the median survival of the non-IVC-TT group (43 months). Current ESMO guidelines recommend excision of recur- rent disease only if patients recur after 12 months from their index operation, and so it may be that limited rate of excision of recurrence in the IVC- TT group serves as a surrogate for the aggressive nature of their disease. 18
A significant limitation of our study is sample size and therefore, this study is underpowered to perform further specific subset analysis. Specific
areas of interest that may or may not affect survival that we were not able to delineate given small sample size were degree of IVC stenosis and the effect of adjuvant chemotherapy on our popula- tion. Additionally we are limited by the retrospec- tive nature of our study. To account for this the Kaplan-Meier method of censoring was used for survival analysis. Also a consistent pathologic grading system during the 30-year period was lacking, and so in-depth analysis of pathologic factors was limited. Additionally, a thorough pre- operative evaluation for distant metastatic disease was attempted in all patients; however, a few patients in each cohort (n = 4 in IVC-TT, n = 6 in non-IVC-TT) did not have a preoperative CT scan of the chest and thus those patients could have had metastatic disease at the time of operation that was unknown. Lastly, selection bias also must be considered given that patients who underwent IVC-TT were likely carefully screened and selected prior to an operation.
Resection requiring IVC tumor thrombectomy seems to have perioperative outcomes and short- term oncologic survival equivalent to patients without IVC-TT. However, patients being evaluated for resection of stage IV non-metastatic ACC with IVC-TT should be carefully selected and counseled as long-term survival is poor, with no survivors in our cohort at 60 months. Despite the inferior long- term oncologic outcomes in patients requiring IVC-TT, the lack of efficacious alternative therapy may justify aggressive resections in these difficult to treat patients.
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DISCUSSION
Dr Richard A. Hodin (Boston, MA): That was a fantastic presentation. We see these are rare tu- mors, so it is great that you were able to gather the data from so many decades.
Can you give us some information about the technical aspects of the operation in terms of the IVC thrombus, how often the resection of the vein, reconstruction and whether that made any difference?
Dr Danuel V. Laan: Sure. If you could bring my slides back up, please. As these are coming up, when we looked at extent of tumor thrombus, we saw that the majority of our patients had tumor thrombus into the infrahepatic IVC, while the next percentage was going up within the retrohe- patic IVC, the suprahepatic IVC and into the atrium. We had 5 patients who needed to go on cardiopulmonary bypass for this operation, and all 5 of those had atrial involvement, as you might expect.
We had one patient who required an IVC tube graft, while the rest of our patients really just required a venotomy with tumor thrombus exci- sion, or a longitudinal incision along the IVC with tumor thrombus removal. So there was a lot of variability in how involved the operation could be, so I think this sort of gives you an idea about how it was divided up in our cohort.
Dr Richard A. Hodin (Boston, MA): I know there were small numbers, but was there a differ- ence in outcome?
Dr Danuel V. Laan: We are not able to do a sub- set analysis due to the limited number and an un- derpowered study with those numbers.
Dr Haggi Mazeh (Jerusalem, Israel): This was a beautiful presentation, and I think we all agree that patients with IVC tumor have a worse prognosis. But from my humble experience, the question is, who do I not operate on? They pre- sent with an IVC tumor, and I know it may be doable, but then some patients just progress while I work them up, or they are simply unre- sectable because of atrial involvement or other things. Do you know which patients you-or do you have any data on the patients that you did not operate on?
Dr Danuel V. Laan: Unfortunately, we do not have data on the patients we did not operate on. And the reason that is, is because we gathered our data from pathologic diagnosis with adrenal cortical cancer. You bring up a very good point on the resection data of patients with IVC tumor thrombus. Right now, obviously, tumor thrombus would be stage 3 if you look at the grading criteria. With this limited survival that we see, would it be prudent to upstage patients with tumor thrombus in stage 4 disease? And that, I think, is a big ques- tion that needs to be answered.
Dr Jeffrey E. Lee (Houston, TX): Thanks for this great presentation highlighting the very poor prognosis of these patients. The often formidable operations need to be done in order to clear their tumors. I am going to ask the neoadjuvant question.
Since we have systemic therapy in the form of a BRACC regimen, for example, that has some demonstrated activity in this disease, and since, in a small retrospective series that we published a year or so ago, we demonstrated significant, about twice the reported response rates in the IVC in particular for patients exactly like you presented. Have you considered giving some of these patients chemo up front and operating later?
Dr Danuel V. Laan: That has not been done at our institution. I think that is a very good point. And to draw on that, in the last 10 years, there has been increase in cytotoxic medication used to treat these tumors.
When we looked at our surgical cohort, we only had about 5-6 patients in each group that were treated with cytotoxic chemotherapy. Ultimately, our numbers were too low to draw conclusions on that. I think the point on neoadjuvant chemo- therapy is important and should be further studied.
Dr Electron Kebebew (Bethesda, MD): No con- flicts of interest. I enjoyed your presentation. Inter- esting data.
I have 2 questions for you. One is related to the postoperative chemotherapy, spans 3 decades, if I am not mistaken. But did any of the patients get modern regimen mitotane with EDP?
The second question is in regards to the functional status of these tumors. Did any of the patients have hypercortisolism?
Dr Danuel V. Laan: With regard to your first question, we did look at that, and what we found was that only 5 patients in our IVC tumor thrombus cohort received the modern regimen of EDP plus mitotane. And this is all based on the trial from about 10 years ago.
When we looked at our non-IVC tumor thrombus cohort, we only had about 4 patients who received that, so we were unable to do a subset analysis of the impact of cytotoxic adjuvant chemo- therapy on our patient group.
With regard to your second question on hyper- cortisolism or cortisol secretion of these adrenal cancers, we had about 45%, roughly similar in both patient groups who presented with a symp- tomatic disease. Of those, about half were pre- senting with signs and symptoms of Cushing syndrome.
Dr Scott M. Wilhelm (Cleveland, OH): Just as a follow-up to the technical question. Were you able to look back? I know you said you had 5 patients that had cardiopulmonary bypass. Were you able to look back and also see whether or not you had multidisciplinary involvement in any of these cases? Because these obviously are complex, some- times even involve either our vascular colleagues, some of our liver colleagues for the retrohepatic for mobilization, and then obviously our cardio- thoracic component. These are great opportu- nities to work with others to get hopefully better outcomes, too.
Dr Danuel V. Laan: I totally agree. On every sin- gle patient we had a cardiopulmonary bypass, we had a multidisciplinary surgical team including vascular and cardiothoracic involved.
Dr Michael J. Demeure (Phoenix, AZ): Did you control for pathology like with Weiss Score? Because you might predispose that a more aggres- sive tumor might be more likely to invade the IVC. If you could shed some light on how dependent Weiss Score or other pathologic criteria was.
Dr Danuel V. Laan: With regard to pathologic grade, we had similar percentages of patients receiving a high pathologic grade in each of our cohorts, those with and without IVC tumor thrombus.
You bring up a good point, though, in the Weiss Pathologic Scoring System. When I reviewed the pathology of these patients, I did not see a consistent pathologic standard way of diagnosing adrenocortical carcinoma at our institution, and I think that is really an area that we can improve is using the Weiss Pathologic Grading System.