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ORIGINAL ARTICLE - ENDOCRINE TUMORS
Differences in Clinicopathologic Behavior of Oncocytic Adrenocortical Neoplasms and Conventional Adrenocortical Carcinomas
Aditya S. Shirali, MD1, Jonathan Zagzag, MD2, Yi-Ju Chiang, MSPH1, He Huang, MD3, Miao Zhang, MD, PhD4, Mouhammed Amir Habra, MD5, Elizabeth G. Grubbs, MD1, Sarah B. Fisher, MD1, Nancy D. Perrier, MD1, Jeffrey E. Lee, MD1, and Paul H. Graham, MD1
1Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; 2St. Francis Hospital and Heart Center, Roslyn, NY; 3Department of Pathology, Baylor University Medical Center, Dallas, TX; 4Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX; 5Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX
ABSTRACT
Background. Oncocytic adrenocortical neoplasms (OANs) are rare endocrine tumors that present as a spec- trum from benign to malignant. The outcomes after surgical resection of the oncocytic variant of adrenocortical carcinoma remain poorly understood. We sought to char- acterize the clinicopathologic features of OAN and compare oncocytic adrenocortical carcinoma (OAC) with conventional adrenocortical carcinoma (ACC).
Patients and Methods. Adult patients who underwent adrenalectomy for OAN or ACC between January 1990 and September 2020 were identified. Demographics, clin- icopathologic factors, American Joint Committee on Cancer stage, and cancer-related outcomes were reviewed. A matched cohort analysis of disease-free survival (DFS) and overall survival (OS) was performed between patients with OACs and those with ACCs.
Results. Forty-one patients with OAN and 214 patients with ACC were included. The OAN cohort median age was 45.2 years [interquartile ratio (IQR) 38.5-54.0 years], and 61.0% were female. OANs were benign (n = 11), of uncertain malignant potential (UMP, n = 9), or OAC (n = 21). Disease recurrence occurred in 12 (57.1%) patients
with OAC compared with 1 (11.1%) and 0 patients with UMP or benign OAN, respectively (p < 0.001). Seven (33.3%) patients with OAC died during follow-up com- pared with 0 patients with UMP or benign OAN (p = 0.020). Kaplan-Meier survival analysis found no differ- ence in DFS between ACC and OAC groups before (p = 0.218) and after 2:1 matching (p = 0.417). Overall survival was shorter for patients who had ACC compared with those who had OAC (p = 0.031), but the difference was not evident with matched analysis (p = 0.200).
Conclusions. OAN presents as a spectrum from benign indolent tumors to aggressive carcinomas. OACs demon- strate similar clinicopathologic behavior and recurrence-free and overall survival when matched to conventional ACCs.
Oncocytic neoplasms are uncommon tumors characterized by abundant granular eosinophilic cytoplasm and mitochon- dria.1 Oncocytic neoplasms have been identified at various anatomic locations throughout the body, but were first described in the adrenal gland in 1986 by Kakimoto et al.2 The clinical behavior and outcomes of oncocytic adrenocortical neoplasms (OANs) as compared with conventional adreno- cortical neoplasms has been difficult to discern given an overlap in pathologic criteria used to characterize adreno- cortical neoplasms and the rarity of these tumors.” 3
In 2004, a modified Weiss classification system, known as the Lin-Weiss-Bisceglia (LWB) criteria, was proposed to standardize evaluation of OANs and refine categorization as benign, of uncertain malignant potential (UMP), or malig- nant.4 Histologically benign oncocytic neoplasms uniformly
@ Society of Surgical Oncology 2022
Published Online: 30 April 2022
demonstrate excellent 5-year outcomes; however, for the approximately 65% of OANs that are classified as either malignant or as harboring uncertain malignant potential,5,6 the clinical behavior is not well characterized.
Earlier reports describe oncocytic adrenocortical carci- noma (OAC) as more indolent in nature compared with conventional ACC, with relatively improved overall sur- vival despite their generally larger tumor size at presentation.79 While these previous studies provide invaluable information regarding the clinical behavior of these rare neoplasms, they are limited by small sample size, different clinical practice patterns, and the inclusion of mixed and borderline oncocytic tumor types. We present a single-institution tertiary referral center experience to compare the clinical presentation, treatment, and outcomes of patients with OAN with specific emphasis on comparing outcomes of pure OACs with conventional ACC.
METHODS
Following institutional review board approval, and in accordance with the Health Insurance Portability and Accountability Act of 1996, patients undergoing either medical or surgical treatment for OAN or ACC between January 1, 1990 and September 1, 2020 were identified from a prospectively maintained tumor registry of all patients with adrenal tumors evaluated at The University of Texas MD Anderson Cancer Center (MDACC). Patients with OANs of any type as well as conventional ACC were identified. Patients were included in the study if the specimens from their primary adrenalectomy were available for pathologic review at our institution. Patients were excluded if they were less than 18 years of age or if we were unable to perform pathologic review of the primary surgical specimen.
Demographics, clinicopathologic factors, site of surgery, surgical technique, American Joint Committee on Cancer (AJCC) 8th edition stage, and cancer-related outcomes were obtained from chart review. Site of surgery was identified as either MDACC or an outside institution. Surgical technique was defined as open anterior resection, minimally invasive resection (laparoscopic transabdominal or retroperitoneoscopic), or minimally invasive converted to open anterior resection. Tumor stage at presentation was determined by the TNM classifications for ACC according to the American Joint Committee on Cancer (AJCC), 8th edition. Disease-free survival (DFS) was defined as the time (in months) from curative-intent resection to the first radiographic or pathologic evidence of local or distant recurrence, or the date of last known follow-up. Patients with distant metastases at primary resection were not included in DFS analysis. Overall survival (OS) was defined as the time (in months) from the date of diagnosis to date of death or last known follow-up.
All primary specimens, whether obtained from surgery at our institution or elsewhere, were reviewed by an experienced adrenal pathologist at our institution at the time of referral and designated according to listed criteria. Specimens were considered oncocytic if more than 75% of neoplastic cells were composed of eosinophilic cells. Specimens with less than 75% (i.e., containing any onco- cytic component as well as a conventional adrenal tumor cell component) oncocytes were considered conventional adrenal tumors, and were excluded from this analysis. The tumors of patients with pure OAN were classified as benign, of uncertain malignant potential (UMP), or onco- cytic adrenocortical carcinoma (OAC) according to the Lin-Weiss-Bisceglia (LWB) criteria, which were formally incorporated at our institution in 2010.4 Prior to 2010, experienced adrenal pathologists incorporated the founda- tions of LWB criteria such as attention to atypical mitoses and venous invasion into the categorization of oncocytic carcinoma as described by Ro and Wu.10 The criteria defined by Wu et al. defined oncocytic UMP as having increased mitotic activity [> 5/50 high-power field (HPF)] or microscopic foci of necrosis and OAC as having nuclear pleomorphism along with atypical mitoses, capsular inva- sion, extratumoral venous invasion, or metastasis.10
Statistical analysis included the use of the Fisher’s exact test or the Wilcoxon rank-sum test where appropriate. Disease-free survival was evaluated by Kaplan-Meier survival curves and Cox proportional hazard models. Fac- tors associated with DFS and OS were identified by univariate analysis and further evaluated by multivariate analysis if p < 0.20. Both Ki67 and number of mitoses were excluded from the survival analyses because of incomplete data. A 2:1 matched cohort analysis was per- formed between patients with ACCs and OACs after matching for patient age, patient sex, AJCC stage, and tumor functionality. All multivariate models used a Cox regression mode with the Firth penalized maximum like- lihood method for adjusting bias correction. All were performed using SAS 9.4 (Cary, NC), with statistical sig- nificance defined as p < 0.05.
RESULTS
Oncocytic Adrenocortical Neoplasms
A total of 647 patients diagnosed with either OAN or conventional ACC met our initial inclusion criteria. Of these patients, 390 were excluded (210 who did not undergo adrenalectomy for their primary tumor and 180 with limited available data). Of the remaining 257 patients, 43 had an OAN and 214 had a conventional ACC. Two patients with OAN had pathologic findings of mixed
oncocytic and conventional histology and were excluded, leaving a total of 41 patients with pure oncocytic adreno- cortical neoplasms (OANs) and 214 patients with conventional ACC. OANs were identified as benign (n = 11), UMP (n = 9), and OAC (n = 21). The preoperative, treatment, and pathologic features of these patients are presented in Table 1. The median age of the OAN cohort was 45.2 years (IQR 38.5-54.0 years), and 61.0% were female. There were no differences in age, sex, race, or laterality of OANs between the three groups (p > 0.05). Functional OANs were found in 18.2% of benign tumors, 55.6% of UMPs, and 42.9% of OACs (p = 0.232). Of the functional tumors, at least 50% were cortisol-producing across all three OAN groups.
There was no statistical difference in the proportion of patients who underwent initial surgery at our institution between the three groups. Resection of OACs or UMPs was more likely to be performed via an open surgical approach as compared with benign OAN (90.4% and 77.8% versus 36.4%, respectively, p = 0.001); OAC and UMP were larger at resection compared with benign OAN [OAC, 11.4 (IQR 7.1-15.0) cm and UMP, 10.0 (IQR 7.0-11.0) cm, respectively versus benign OAN, 5.0 (IQR 3.5-8.0) cm, p = 0.002]. Resected specimens of OAC were more likely to have higher Ki67 (p <0.05) and mitotic rate greater than 5/50 high-power fields (p < 0.001) than UMP or benign OAC; however, Ki67 and mitotic rate indices were not available for 14 (34.1%) and 5 (12.2%) patients, respectively. Nineteen (73.1%) patients with OAC received mitotane compared with 1 (11.1%) UMP patient and 0 patients with benign OAN (p < 0.001).
The median follow-up of the OAN cohort was 37.5 months (IQR 25.1-68.0 months). Twelve patients (57.1%) with OAC developed recurrent disease following resection compared with 1 (11.1%) patient with UMP and 0 patients with benign OAN (p < 0.001). There was no difference in median follow-up between UMP [62.2 (IQR 26.1-202.0) months] and OAC [37.4 (IQR 27.6-68.0) months, p = 0.53]. The single patient classified as having a UMP who developed recurrence presented with a tumor 6.4 cm in size and Ki67 proliferative index of 20%; the patient developed pulmonary metastases 53 months following primary tumor resection. Seven (33.3%) patients with OAC died during follow-up compared with 0 patients with UMP or benign tumors (p = 0.020).
Oncocytic and Conventional Adrenocortical Carcinoma
A total of 214 patients with conventional ACC who met the inclusion criteria were compared with the 21 patients with OAC. The preoperative, treatment, and pathologic features of patients with ACC and OAC are presented in
Table 2. There were no statistically significant differences in age, sex, race, tumor laterality, tumor functionality, metastases at diagnosis, site of initial surgery, initial sur- gical technique, mitotane therapy, tumor size at resection, AJCC stage, resection margins, or Ki67 between patients with ACC and OAC (p > 0.05). Data regarding Ki67 were only available for 67 ACC and 13 OAC patients. Patients with ACC were more likely to have more than 5/50 HPF mitoses compared with those with OAC [78 (83%) versus 11 (52.4%), p = 0.017] and had higher median number of mitoses compared with patients with OAC [25 mitoses (IQR 9-65) versus 7.5 (IQR 2-19), p = 0.003], although data regarding mitotic rate were only available for 94 patients with ACC and 18 with OAC.
Recurrence and Mortality of OACs and ACCs
There was no statistically significant difference in median follow-up between patients with ACC [34.7 (IQR 18.3-75.1) months] and those with OAC [37.4 (IQR 27.6-68.0) months, p = 0.541]. Ten patients (47.6%) with OAC developed locoregional recurrence compared with 71 (33.2%) patients with ACC (p = 0.230). Nine patients (42.9%) with OAC developed distant metastases compared with 137 patients (64.0%) with ACC (p = 0.063). While patients with OAC tended to have a longer median time to recurrence compared with patients with ACC (24.9 months versus 11.3 months), this association was not statistically significant (p = 0.218, Fig. 1A). Median OS was longer for patients with OAC (121.2 months) compared with those with ACC (46.0 months) (p = 0.031, Fig. 1B).
Table 3 presents the results of univariate and multi- variate analyses for DFS and OS of the combined adrenal carcinoma cohort including patients with conventional ACC or OAC. On univariate analysis, tumor functionality [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.23-2.33, p = 0.001] and mitotane therapy (HR 2.56, 95% CI 1.56-4.20, p < 0.001) were found to be associated with poorer DFS. Similarly, multivariate analysis identified tumor functionality (HR 1.44, 95% CI 1.04-1.99, p = 0.028), and mitotane therapy (HR 2.21, 95% CI 1.33-3.68, p = 0.002) to be independently associated with poorer DFS. Oncocytic histology was not associated with improved DFS. On univariate analysis, right-sided carcinoma (HR 0.66, 95% CI 0.48-0.92, p = 0.014), mitotane therapy (HR 0.68, 95% CI 0.48-0.97, p = 0.031), and oncocytic his- tology (HR 0.44, 95% CI 0.21-0.95, p = 0.036) were associated with improved OS, while tumor functionality (HR 1.79, 95% CI 1.30-2.49, p < 0.001) was associated with poorer OS. Of these, only tumor functionality (HR 1.79, 95% CI 1.30-2.49, p = 0.002) was independently associated with OS on multivariate analysis; oncocytic histology (HR 0.49, 95% CI 0.23-1.05, p = 0.066) trended
| Benign (n = 11) | UMP (n = 9) | Carcinoma (n = 21) | p value | |
|---|---|---|---|---|
| Preoperative characteristics | ||||
| Age (year) | 42 (34-44) | 45 (42-48) | 51 (39-60) | 0.107 |
| Sex | 0.152 | |||
| Female | 6 (54.6%) | 8 (88.9%) | 11 (52.4%) | |
| Male | 5 (45.4%) | 1 (1.1%) | 10 (47.6%) | |
| Race | 0.167 | |||
| White | 10 (90.9%) | 6 (66.7%) | 20 (95.2%) | |
| Black | 0 | 2 (22.2%) | 1 (4.8%) | |
| Asian | 1 (9.1%) | 1 (11.1%) | 0 | |
| Other/declined | 0 | 0 | 0 | |
| Laterality of primary | 0.187 | |||
| Left | 4 (36.4%) | 7 (77.8%) | 11 (52.4%) | |
| Right | 7 (63.6%) | 2 (22.2%) | 10 (47.6%) | |
| Functional | 2 (18.2%) | 5 (55.6%) | 9 (42.9%) | 0.232 |
| Cortisol-producing | 1 (50%) | 3 (60%) | 8 (88.9%) | 0.137 |
| Treatment characteristics | ||||
| Site of initial surgery | 0.555 | |||
| MDACC | 6 (54.6%) | 5 (55.6%) | 9 (34.6%) | |
| Outside facility | 5 (45.4%) | 4 (44.4%) | 13 (61.9%) | |
| Initial surgical technique | 0.002 | |||
| Open | 4 (36.4%) | 7 (77.8%) | 19 (90.4%) | |
| Minimally invasive (MIS) | 7 (63.4%) | 2 (22.2%) | 4 (4.8%) | |
| MIS conversion to open | 0 | 0 | 4 (4.8%) | |
| Mitotane | 0 | 1 (11.1%) | 14 (66.7%) | < 0.001 |
| Neoadjuvant | 0 | 2 (14.3%) | 0.999 | |
| Adjuvant | 1 (100%) | 7 (50.0%) | 0.999 | |
| Pathologic features | ||||
| Tumor size at resection (cm) | 5.0 (3.5-8.0) | 10.0 (7.0-11.0) | 11.4 (7.1-15.0) | 0.002 |
| Stage | < 0.001 | |||
| I | 7 (63.6%) | 0 | 1 (4.8%) | |
| II | 4 (36.4%) | 9 (100%) | 11 (52.4%) | |
| III | 0 | 0 | 6 (28.6%) | |
| IV | 0 | 0 | 3 (14.2%) | |
| Resection margins | 0.581 | |||
| R0 | 10 (90.9%) | 9 (100%) | 14 (66.7%) | |
| R1 | 0 | 0 | 3 (14.3%) | |
| R2 | 0 | 0 | 1 (4.8%) | |
| RX | 1 (9.1%) | 0 | 3 (14.3%) | |
| Ki67 | 4.5 (2.0-9.0) | 5.1 (4.6-11.7) | 17.0 (7.5-32.0) | 0.027 |
| Number of mitoses (> 5/50 HPF) | 0 | 0 | 11 (52.4%) | < 0.001 |
| Recurrence | 0 | 1 (11.1%) | 12 (57.1%) | < 0.001 |
| Mortality | 0 | 0 | 7 (33.3%) | 0.02 |
OAN oncocytic adrenocortical neoplasm, UMP uncertain malignant potential, MDACC MD Anderson Cancer Center, MIS minimally invasive surgery, HPF high-power field
toward being associated with improved OS in multivariate analysis, but was not statistically significant.
To further evaluate the relationship between OAC his- tology and outcome in patients with ACC, a 2:1 matched
cohort analysis was performed; in this analysis, no differ- ence in DFS or OS was identified (Fig. 1C, D). Median DFS was 14.9 months in patients with conventional ACC versus 33.3 months in patients with OAC (p = 0.417).
| Conventional adrenocortical carcinoma (n = 214) | Oncocytic adrenocortical carcinoma (n = 21) | p value | |
|---|---|---|---|
| Preoperative characteristics | |||
| Age (year) | 48 (36-56) | 51 (39-60) | 0.271 |
| Sex | 0.349 | ||
| Female | 136 (63.6%) | 11 (52.4%) | |
| Male | 78 (36.4%) | 10 (47.6%) | |
| Race | 0.323 | ||
| White | 178 (83.2%) | 20 (95.2%) | |
| Black | 6 (2.8%) | 1 (4.8%) | |
| Asian | 6 (2.8%) | 0 | |
| Other/declined | 24 (11.2%) | 0 | |
| Laterality of primary | > 0.999 | ||
| Left | 111 (51.9%) | 11 (52.4%) | |
| Right | 103 (48.1%) | 10 (47.6%) | |
| Functional | 101 (47.2%) | 9 (42.9%) | 0.82 |
| Cortisol-producing | 72 (71.3%) | 8 (88.9%) | 0.443 |
| Metastases at diagnosis | 37 (17.3%) | 3 (14.3%) | > 0.999 |
| Location of metastases* | |||
| Lung | 20 (9.3%) | 3 (14.3%) | 0.727 |
| Liver | 22 (10.3%) | 1 (4.8%) | 0.812 |
| Bone | 5 (2.3%) | 0 | 0.708 |
| Distant lymph node | 4 (1.9%) | 0 | 0.632 |
| Other | 1 (0.47%) | 0 | 0.754 |
| Treatment characteristics | |||
| Site of initial surgery | 0.654 | ||
| MDACC | 64 (29.9%) | 8 (38.1%) | |
| Outside facility | 150 (70.1%) | 13 (61.9%) | |
| Initial surgical technique | 0.697 | ||
| Open | 179 (83.6%) | 19 (90.5%) | |
| Minimally invasive | 25 (11.7%) | 1 (4.8%) | |
| MIS conversion to open | 10 (4.7%) | 1 (4.8%) | |
| Mitotane | 179 (83.6%) | 14 (66.7%) | 0.056 |
| Neoadjuvant | 13 (7.3%) | 2 (14.3%) | 0.244 |
| Adjuvant | 94 (52.5%) | 7 (33.3%) | 0.777 |
| Pathologic features | |||
| Tumor size at resection (cm) | 11.0 (8.5-15.0) | 12 (9.5-15.0) | 0.498 |
| Stage | 0.441 | ||
| I | 7 (3.3%) | 1 (4.8%) | |
| II | 79 (36.9%) | 11 (52.4%) | |
| III | 91 (42.5%) | 6 (28.6%) | |
| IV | 37 (17.3%) | 3 (14.3%) | |
| Resection margins | 0.87 | ||
| R0 | 121 (56.5%) | 14 (66.7%) | |
| R1 | 44 (20.6%) | 3 (14.3%) | |
| R2 | 10 (4.7%) | 1 (4.8%) | |
| RX | 39 (18.2%) | 3 (14.3%) | |
| Ki67 | 25 (14.5-40.0) | 17 (7.5-32.0) | 0.187 |
| Conventional adrenocortical carcinoma (n = 214) | Oncocytic adrenocortical carcinoma (n = 21) | p value | |
|---|---|---|---|
| Number of mitoses (> 5/50 HPF) | 78 (83.0%) | 11 (52.4%) | 0.035 |
| Number of mitoses | 25 (9-65) | 7.5 (2-19) | 0.003 |
*Denominator is the number of patients with conventional ACC or OAC
(a)
Disease-Free Survival (%)
(b)
100
ACC
100
ACC
OAC
Overall Survival (%)
OAC
p=0.218
p=0.031
50
50
0
0
0
25
50
75
100
125
150
0
25
50
75
100
125
150
Time (months)
Time (months)
No. at risk
ACC
214
139
84
57
40
19
11
OAC
21
18
9
5
5
3
3
(c)
100
7
ACC
(d)
100
7
ACC
Disease-Free Survival
OAC
Overall Survival (%
OAC
p=0.417
p=0.200
50
50
0
0
0
25
50
75
100
0
25
50
75
100
125
150
Time (months)
Time (months)
No. at risk
No. at risk
ACC
41
16
9
6
4
ACC
42
31
24
15
12
6
4
OAC
18
11
2
0
0
OAC
21
18
9
5
5
3
2
| No. at risk ACC | 189 | 58 | 9 | 6 | |||
|---|---|---|---|---|---|---|---|
| 38 | 29 | 19 | |||||
| OAC | 18 | 9 | 2 | 0 | 0 | 0 | 0 |
Median OS was 70.2 months in patients with conventional ACC versus 121.2 months in those with OAC (p = 0.200) on matched analysis. Univariate analysis identified only tumor functionality to be associated with poorer DFS (HR 2.92, 95% CI 1.50-5.68, p = 0.001) and OS (HR 2.07, 95% CI 1.05-4.07, p = 0.035); oncocytic histology was not associated with improved DFS (HR 0.89, 95% CI 0.43-1.83, p = 0.749) or OS (HR 0.53, 95% CI 0.23-1.23, p = 0.138) compared with conventional ACC. Multivariate modeling was not performed owing to the limited number of events.
DISCUSSION
We describe the evaluation of a relatively large single- institution population of patients with oncocytic adreno- cortical neoplasm (OAN), and present evidence suggesting that pure OAC may behave in a similar manner to con- ventional ACC.
This study highlights the overall favorable outcome of patients with benign or uncertain malignant potential oncocytic pathology. All patients with benign or UMP OANs in our cohort survived, and one patient with UMP developed distant metastasis at 53 months postoperatively. Patients with UMP require continued radiographic and biochemical, if appropriate, surveillance given the small risk for late recurrence, despite excellent survival, while patients with benign OANs require no further surveillance given the low risk of recurrence.
Recent literature has suggested that oncocytic histology confers a more indolent biology compared with conven- tional ACC, with longer reported median time to recurrence and a trend toward longer overall survival in OAC.8 Renaudin et al. compared 43 patients with onco- cytic adrenocortical tumors (6 UMP and 28 OAC by LWB criteria) with 37 patients with conventional ACC and found improved OS (92% versus 56% at 2 years) in patients with oncocytic histology compared with patients with
| Disease-free survival | Overall survival | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | |||||||||
| Hazard Ratio | 95% CI | p value | Hazard Ratio | 95% CI | p value | Hazard Ratio | 95% CI | p value | Hazard Ratio | 95% CI | p value | |
| Age (year) | 0.99 | 0.98-1.01 | 0.392 | – | – | – | 1.01 | 0.99-1.02 | 0.078 | – | – | – |
| Sex | 0.78 | 0.56-1.08 | 0.134 | – | – | – | 0.74 | 0.53-1.04 | 0.085 | – | – | – |
| Race (versus White) | 0.554 | 0.595 | ||||||||||
| Black | 0.39 | 0.10-1.58 | – | – | – | 0.65 | 0.21-2.06 | – | – | – | ||
| Asian | 1.09 | 0.35-3.44 | – | – | – | 1.12 | 0.36-3.54 | – | – | – | ||
| Other/declined | 1.14 | 0.69-1.86 | – | – | – | 0.70 | 0.39-1.27 | – | – | – | ||
| Laterality of primary (right versus left) | 0.87 | 0.64-1.18 | 0.375 | – | – | – | 0.66 | 0.48-0.92 | 0.014 | – | – | – |
| Functional | 1.69 | 1.23-2.33 | 0.001 | 1.44 | 1.04-1.99 | 0.028 | 1.79 | 1.30-2.49 | < 0.001 | 1.69 | 1.21-2.36 | 0.002 |
| Surgical technique (open versus | 0.87 | 0.53-1.40 | 0.557 | – | – | – | 0.69 | 0.20-1.20 | 0.189 | – | – | – |
| laparoscopic) | ||||||||||||
| Tumor size | 1.01 | 0.98-1.05 | 0.534 | – | – | – | 1.02 | 0.98-1.05 | 0.361 | – | – | – |
| Stage | ||||||||||||
| II-IV versus I | 1.99 | 0.82-4.88 | 0.194 | – | – | – | 1.52 | 0.56-4.10 | 0.411 | – | – | – |
| III/IV versus I/II | 1.23 | 0.89-1.69 | 0.129 | 1.56 | 0.63-3.87 | 0.336 | 1.36 | 0.93-1.90 | 0.069 | 1.21 | 0.86-1.70 | 0.264 |
| Resection margin (R1 and R2 versus R0) | 1.34 | 0.99-2.17 | 0.153 | – | – | – | 1.47 | 0.99-2.17 | 0.153 | – | – | – |
| Mitotane therapy | 2.56 | 1.56-4.20 | < 0.001 | 2.21 | 1.33-3.68 | 0.002 | 0.68 | 0.48-0.97 | 0.031 | – | – | – |
| Oncocytic histology | 0.69 | 0.38-1.25 | 0.221 | – | – | – | 0.44 | 0.21-0.95 | 0.036 | 0.49 | 0.23-1.05 | 0.066 |
conventional ACC.9 Mitoses > 5/50 HPF were present in 53.4% of the oncocytic cohort with a mean Ki67 index of 3.5%. Of note, only 65% of oncocytic tumors were noted to be pure, resulting in inclusion of 2 pure UMPs and 22 pure OACs. Our study shows similar morphologic characteris- tics in our pure oncocytic cohort, with only 52.4% of patients with mitoses > 5/50 HPF compared with 83.0% among patients with conventional ACC. Nevertheless, our study found no difference in DFS and OS among patients with OAC and ACC after 2:1 cohort matching by age, sex, tumor functionality, and AJCC stage despite an overall similar number of patients studied. Taken together, our findings question the previously described improved out- comes in patients with OAC.
Our data demonstrate that high Ki67 and mitoses more than 5/50 HPF may serve as important factors associated with OACs compared with other OANs. Several studies have demonstrated that the use of morphologic criteria, such as mitoses and presence of necrosis, and Ki67 immunohistochemistry for prognostication of ACCs is reproducible,11-14 and the combined use of these variable may outperform the sole use of Ki67 in prognostication of ACCs.15,16 The higher Ki67 index in our cohort of OACs compared with that of the Renaudin et al. group (17.5% versus 3.5%, respectively) may account for the difference in survival we see when comparing patients with OAC versus patients with conventional ACC between the two studies,9 and highlights the importance of its incorporation into prognostication of OAC. However, the inconsistent reporting of Ki67 among conventional ACCs over the study period precluded our ability to incorporate this index in our multivariate analysis.
Our univariate and multivariate analyses of DFS and OS among our combined adrenal carcinoma cohort showed that oncocytic histology was not associated with improved DFS. While oncocytic histology was associated with improved OS on univariate analysis, there was no longer a statistically significant association after controlling for other variables on multivariate analysis. Furthermore, after matching OAC and ACC for age, sex, AJCC stage, and tumor functionality, oncocytic histology was not associated with improved DFS or OS. We also show that the use of mitotane therapy was independently associated with poorer DFS. This finding does not suggest that mitotane is pre- dictive of disease progression, but rather that patients following resection with a higher risk of recurrence based on European Society of Endocrinology (ESE) and ENSAT 2018 guidelines (i.e., stage III, R1 resection, or Ki67 > 10%) or who later recurred were given mitotane and that mitotane use is serving as a surrogate for more aggressive disease biology at presentation.17,18 This study was not designed to determine the role of mitotane in predicting DFS or OS.
Our study suffers from the inherent limitations and biases attributed to single-center, retrospective studies. Adoption of the Lin-Weiss-Bisceglia (LWB) criteria4 was actively incorporated into the histopathologic diagnosis of OAN at our institution starting around 2010, questioning differences between time periods. Specific comparison of DFS and OS between OACs diagnosed before 2010 and after 2010, however, shows no difference (data not shown), suggesting that the incorporation of LWB criteria at our institution did not significantly alter the pattern of stratifi- cation of OANs. Similarly, standard collection of mitotic rate and proliferative indices earlier in the 30-year time period was not performed, limiting our ability to incorpo- rate these variables into multivariate analysis and assess their ability to predict aggressive behavior of OACs. Additionally, approximately 62% and 70% of the adrenalectomies for OAC and ACC, respectively, were initially performed outside our institution and later referred to our institution for further management. This introduces referral bias and may reflect more aggressive disease among patients with OAC referred to our institution for specialty care, though specific comparison of DFS and OS between both groups stratified by initial treatment location showed no difference (data not shown). Finally, as is the case with previous studies examining patients with OAN, our study is limited by the rarity of the disease entity and the small number of patients included. Nevertheless, we provide one of the largest cohorts of surgically resected OANs and conventional ACCs for comparison.
CONCLUSIONS
We present a single-institutional experience examining the clinicopathologic behavior of OAN and compare pure OAC with one of the largest reported cohorts of surgically resected conventional ACC. Contrary to previous studies, we find that oncocytic histology does not confer indolent biological behavior. Rather, patients with pure OAC have similar DFS and OS compared with patients with con- ventional ACC after matching for age, sex, tumor functionality, and AJCC stage. While the role of morpho- logic and immunohistochemical criteria for prognosticating UMP and OAC remains to be investigated, we show that OAC does not confer a survival advantage over conven- tional ACC and may, in fact, benefit from similar postoperative management.
DISCLOSURES The authors declare that they have no conflict of interest.
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