Oncocytic Adrenal Neoplasms: Clinical Profiles and Long-Term Outcomes
Alaa Sada, MD, MS1,2(D, Josiane Joseph, MD3, Reem Alsibai, MD2, Elizabeth B. Habermann, PhD, MPH2, Trenton R. Foster, MD’, Melanie L. Lyden, MD’, Benzon M. Dy, MD’, Irina Bancos, MD4, and Travis J. Mckenzie, MD’
The American Surgeon™ 2025, Vol. 91 (3) 381-385 @ The Author(s) 2024 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/00031348241292727
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Abstract
Background: Oncocytic adrenal neoplasms, defined by ≥90 % of oncocytic cells, are rare. The significance of oncocytic changes within an adrenal neoplasm remains unclear.
Methods: A retrospective study of adults who underwent adrenalectomy at a large center identified pure oncocytic neoplasms on final pathology (1997-2022). Neoplasms were categorized based on Lin-Weiss-Bisceglia system as malignant, benign, or of uncertain malignant potential. Analysis was performed using Fisher exact, Kruskal-Wallis tests, and Kaplan-Meier analysis.
Results: Among a total of 33 patients, 24% had benign, 36% malignant, and 39% neoplasm of uncertain malignant potential. None of the benign neoplasms recurred, while 50% of the malignant neoplasms recurred (median of 40 months). Two of 13 neoplasms initially thought to be of uncertain malignant potential recurred as distant metastatic adrenocortical carcinoma at 1 1 and 25 months, over a median follow-up duration of 31 months. Ki67% was available for 20 patients: median (IQR) Ki67% was 5 (1, 5) for benign, 10 (6, 15) for malignant, and 6.5 (5, 10) for neoplasms of uncertain behavior, P = 0.05. Recurred neoplasms had higher Ki67% at initial resection compared to cases that did not recur.
Conclusion: While oncocytic adrenal neoplasms are rare, a significant proportion are malignant or have malignant potential. Judicious follow-up is required for oncocytic adrenal neoplasms of uncertain malignant potential, as they can recur as metastatic adrenocortical carcinoma. Ki67% should always be obtained in cases of malignancy or uncertain malignant potential as it can predict recurrence. Larger studies are needed to evaluate the appropriate follow-up protocols for these neoplasms.
Keywords
oncocytic, adrenal, adrenocortical carcinoma
Key Takeaways
· Oncocytic adrenal neoplasms are rare and a sig- nificant proportion of them are malignant or have malignant potential.
· Ki67% is a predictor of recurrence in malignant oncocytic adrenal neoplasms or in cases with un- certain malignant potential.
· Judicious follow-up is necessary for oncocytic ad- renal neoplasms of uncertain malignant potential.
Introduction
Oncocytic adrenal neoplasms are a rare type of adrenal tumor that was first described in 1986. They are
composed of eosinophilic cells with abundant granular cytoplasm, resulting from the accumulation of mito- chondria. Their clinical characteristics remain poorly understood due to their rarity, and little is known about their long-term outcomes. There has been increased
‘Department of Surgery, Mayo Clinic, Rochester, MN, USA
2Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
3Mayo ClinicAlix School of Medicine, Rochester, MN, USA
4Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
Corresponding Author:
Travis J. Mckenzie, MD, Department of Surgery, Mayo Clinic, Rochester, MN, 200 1st ST SW, Rochester, MN 55905, USA. Email: Mckenzie. Travis@mayo.edu
interest in studying these neoplasms and understanding their clinical profiles due to their challenging clinical and histological features.2 Given their histological appearance and diffuse growth patterns, the diagnosis of malignancy in these neoplasms cannot be determined by the well- established Weiss and modified Weiss scoring system; instead it relies on the Lin-Weiss-Bisceglia system which categorizes these neoplasms as benign, malignant, or of uncertain malignant potential.3
The Lin-Weiss-Bisceglia scoring system entails major (mitoses > 5 per 50 high-power fields, atypical mitosis, or vascular invasion) and minor criteria (large size >10 cm or >200 g, necrosis, capsular invasion, or sinusoidal invasion).3,4 The diagnosis of malignancy in oncocytic neoplasms requires at least one major criterion, while benign oncocytic cortical adenoma requires the absence of any major or minor criteria. The presence of at least one minor criterion would indicate a neoplasm of uncertain malignant potential.3,4 It should be emphasized that Lin- Weiss-Bisceglia criteria need to be utilized for pure on- cocytic adrenal neoplasms, which comprise at least 90% of oncocytic cells.3 While several case series have de- scribed the clinical characteristics and outcomes of on- cocytic adrenal neoplasms, published data about pure oncocytic neoplasms are extremely limited. Herein, we aim to describe the clinical course and outcomes of pure oncocytic adrenal neoplasms diagnosed at a tertiary high- volume adrenal center.
Methods
A retrospective review of all adults who underwent adre- nalectomy at a large tertiary center between 1/1/1997 and 12/ 30/2022 identified all cases determined to be oncocytic adrenal neoplasms on the final pathology reports. All pa- thology specimens were examined by high-volume endo- crine pathologists. Only pure oncocytic neoplasms, defined by the presence of greater than 90% oncocytic cells, were included, and neoplasms were categorized based on the Lin- Weiss-Bisceglia criteria into benign, malignant, or of un- certain malignant potential. The size of each neoplasm was recorded as the largest dimension on the final pathology report. Neoplasms were further categorized as functional if they were cortisol-secreting, androgen-secreting, mineralocorticoid-secreting, or secreted a mix of more than one hormone. Neoplasm enhancement was measured on the non-contrast phase of the CT scan. This study was ap- proved by the Institutional Review Board (IRB) and in- cluded patients with Minnesota research authorization.
Time to recurrence was calculated from the date of complete surgical resection (R0) to the date of the first recurrence detected on cross-sectional images and was analyzed using Kaplan-Meier analysis and log-rank test. Overall survival (OS) was calculated from the date of surgery to the date of last follow-up or death.
Comparison was performed using Fisher exact and Kruskal-Wallis tests. All analysis was performed using JMP PRO, version 17, SAS Institute Inc., Cary, NC, 1989-2023.
Results
Out of 2941 adrenalectomies performed over the study period, a total of 33 patients with pure oncocytic adrenal neoplasms were identified. The median (IQR) age was 45 years, and 19 (58%) were females. Among the cases, 8 (24%) were benign, 12 (36%) were malignant, and 13 (39%) were neoplasms of uncertain malignant potential. Table 1 summarizes baseline characteristics of the entire cohort.
Non-contrast CT scan results were available for 19 cases. The median adrenal neoplasm enhancement was in the indeterminate category (HU > 10) in all cases and did not differ between benign, malignant, and uncertain malignant potential neoplasms, as shown in Table 1. None of the oncocytic neoplasms enhances less than 10 HU on the non-contrast phase.
The median (IQR) neoplasm size was 36 mm (7.4, 48), 102.5 mm (72.2, 153.75), and 90.8 mm (68.9, 101.5) for benign, malignant, and uncertain malignancy potential, respectively (P<0.01). Ki67% was reported for 20 cases. The median (IQR) Ki67% was 5 (1, 5) for benign, 10 (6, 15) for malignant, and 6.5 (5, 10) for uncertain malignant potential (P = 0.05).
The median (IQR) follow-up duration was 31 (12.5, 59) months. The median overall survival (OS) for the malignant and uncertain malignant cases was 180 months while the median disease-free survival was 117 months (Figure 1).
None of the benign neoplasms recurred after resection, while 50% of the malignant neoplasms recurred, with all but one recurrence being at distant sites. Two of the 13 neoplasms initially thought to be of uncertain malignant potential re- curred as distant metastatic adrenocortical carcinoma at 11 and 25 months. Recurred neoplasms had a higher Ki67% at the initial resection compared to cases that did not recur: the median (IQR) Ki67% was 15 (7.5, 19) for recurred vs 6 (5, 10) for non-recurred neoplasms (P = 0.04).
Open resection was performed in approximately 52% of the malignant cases and cases with uncertain malignant potential, while the rest underwent a minimally invasive approach. In this small cohort, there was no difference in disease-free survival (DFS) between patients who had open vs minimally invasive surgery, P > 0.05.
Discussion
The histopathological features of oncocytic adrenal ne- oplasms are well-established, yet their clinical im- plications are less thoroughly described. Our study examined a series of 33 pure oncocytic adrenal neoplasms
| All N = 33 | Benign N = 8 | Malignant N = 12 | Uncertain N = 13 | P-Value | |
|---|---|---|---|---|---|
| Age | 0.85 | ||||
| Mean ± SD | 48.8 ± 19.3 | 50.6 ± 17.2 | 50.2 ± 20.7 | 46.4 ± 20.5 | |
| Median (IQR) | 45 (31.5, 65) | 46.5 (38.2, 59.2) | 48.5 (30.5, 69.5) | 43 (30.5, 67) | |
| Range | 18, 85 | 29, 85 | 25, 81 | 18, 79 | |
| Sex, % | 0.35 | ||||
| Male | 14 (42.4%) | 5 (62.5%) | 5 (41.7%) | 4 (30.8%) | |
| Female | 19 (57.6%) | 3 (37.5%) | 7 (58.3%) | 9 (69.2%) | |
| Laterality, % | 0.26 | ||||
| Right | 12 (36.4%) | 1 (12.5%) | 5 (41.7%) | 6 (46.2%) | |
| Left | 21 (63.6%) | 7 (87.5%) | 7 (58.3%) | 7 (53.8%) | |
| Functional, % | 0.66 | ||||
| N | 27 | 8 | 9 | 10 | |
| Yes | 16 (59.3%) | 4 (50%) | 5 (55.6%) | 7 (70%) | |
| No | 11 (40.7%) | 4 (50%) | 4 (44.4%) | 3 (30%) | |
| Neoplasm size, mm | <0.01 | ||||
| Mean ± SD | 83.7 ± 52.8 | 29.5 ± 19.7 | 114.8 ± 56.9 | 88.2 ± 35.9 | |
| Median (IQR) | 85 (43.5, 106.5) | 36 (7.4, 48) | 102.5 (72.2, 153.7) | 90.8 (68.8, 101.5) | |
| Range | 2, 250 | 5,52 | 45, 250 | 25, 150 | |
| Ki67% | 0.05 | ||||
| N | 20 | 3 | 7 | 10 | |
| Mean ± SD | 8.1 ± 4.5 | 3.7 ± 2.3 | 10.4 ± 5.4 | 7.8 ± 3.4 | |
| Median (IQR) | 6.5 (5, 10) | 5 (1, 5) | 10 (6, 15) | 6.5 (5, 10) | |
| Range | 1,20 | 1,5 | 5, 20 | 5, 15 | |
| HU on non-contrast CT scan | |||||
| N | 19 | 5 | 7 | 7 | 0.43 |
| Mean ± SD | 36.5 ± 11.1 | 34.4 ± 4.7 | 38.2 ± 7.8 | 36.3 ± 17.0 | |
| Median (IQR) | 35 (31, 37.8) | 35 (30, 38.5) | 36 (34, 37.8) | 33.1 (26.8, 40) | |
| Range | 19, 72 | 29, 41 | 31, 55 | 19, 72 | |
HU = Hounsfield units.
resected at a large tertiary center. We found that oncocytic adrenal neoplasms of uncertain malignant potential have the capability for malignancy and can recur after complete resection as metastatic adrenocortical carcinoma. In- terestingly, we observed that while neoplasms of uncertain malignant potential do not exhibit histological features to clearly categorize them as malignant, Ki67% is an im- portant prognostic tool for predicting recurrence. Given its significance, Ki67% should always be obtained in cases of malignancy or potential for malignancy.
Despite well-established pathological criteria for identifying oncocytic adrenal neoplasms, their clinical management, particularly in cases of uncertain malignant potential, remains challenging due to limited outcome and prognosis data.3,4 Our study showed that 2 out of 13 cases of uncertain malignant potential recurred as distant metastatic adrenocortical carcinoma. Interestingly, we found that Ki67% of the recurrent neoplasms tended to be higher than those without recurrence and therefore, we recommend that Ki67% should always be obtained in cases of malignancy or uncertain malignant potential. Our findings are consistent with other studies. Shirali et al
evaluated the clinical behavior of 41 oncocytic adrenal neoplasms, including 9 cases of uncertain malignant po- tential and reported that 1 out of 9 recurred at 53 months as distant metastatic adrenocortical carcinoma.5 Similar to our study, they found that Ki67% was higher in malignant or uncertain malignant potential cases compared to benign neoplasms.5 Several other studies have shown the prog- nostic value of Ki67% in predicting recurrence and survival for adrenocortical tumors in general and oncocytic adrenal neoplasm in particular.6,7 A multi-institutional retrospec- tive clinicopathologic study included 43 patients with oncocytic adrenal neoplasms and reported worse survival outcomes in neoplasms with higher Ki67% levels.7
In our series, we found that the majority of pure on- cocytic adrenal neoplasms are malignant or of uncertain malignant potential, with only about 24% being benign. This finding is supported by other studies. A systematic review of 140 cases of oncocytic adrenocortical neo- plasms found that the majority of these cases were ma- lignant or borderline, with rates of the benign, borderline, and malignant neoplasms being 35%, 41%, and 24%, respectively.8 The optimal follow-up algorithms for these
100%
···· Malignant
- Uncertain behavior
80%
Survival %
60%
40%
20%
0%
0
20
40
60
80
100
Disease-free survival (months)
neoplasms are not standardized. However, as our study, along with other papers suggest that most of these neo- plasms have malignant potential, we recommend judi- cious periodic follow-up for these cases.
Our results indicate favorable overall outcomes for on- cocytic adrenocortical neoplasms. The recurrence rate fol- lowing R0 resection of oncocytic adrenocortical carcinoma was 50%, while recurrences observed in 2 out of 13 cases of uncertain malignant potential. Historically, the recurrence rate of adrenocortical carcinoma is reported to be 60%-70% after R0 resection, which supports our finding that oncocytic adrenocortical carcinoma tends to have better disease-free survival.6 Shirali et al compared outcomes of 21 cases of oncocytic adrenocortical carcinoma to 214 cases of con- ventional adrenocortical carcinoma and reported a longer median overall survival of oncocytic neoplasms (121 months) compared to conventional cases (46 months).5 Another study included 82 patients with adrenocortical carcinoma, of whom 22% were oncocytic subtypes, and found that compared to the total group of cases, oncocytic neoplasms tend to have better overall survival and disease-free survival.9
Our study has limitations inherent to the retrospective design. Additionally, given that oncocytic adrenal neoplasms are rare, the total number of cases was too small to perform multivariable analysis of factors associated with recurrence and outcomes. Moreover, Ki67% was not available for all cases, and we were underpowered to detect a significant difference in Ki67% between the different groups.
In conclusion, a significant proportion of oncocytic adrenal neoplasms are malignant or have malignant po- tential. Judicious follow-up is required for oncocytic adrenal neoplasms of uncertain malignant potential, as they can recur as metastatic adrenocortical carcinoma. Ki67% should always be obtained in cases of malignancy or uncertain malignant potential as it can predict
recurrence. Larger studies are needed to evaluate the appropriate follow-up protocols for these neoplasms.
Meeting: The 19th Annual Academic Surgical Con- gress in Washington, DC from February 6-8, 2024.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with re- spect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Alaa Sada @ https://orcid.org/0000-0002-6000-5597
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