Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms: a case series and literature review

in Endocrine Oncology
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  • 1 Academic Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
  • | 2 Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
  • | 3 Department of Histopathology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
  • | 4 Department of Pathology, University of Cambridge, Cambridge, UK
  • | 5 Department of Radiology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
  • | 6 Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  • | 7 East Anglian Medical Genetics Service, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

Correspondence should be addressed to E Fewings: elliefewings@hotmail.co.uk

*(E Fewings and S Khoo Sert Kim contributed equally to this work)

Open access

Background

Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behaviour compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours, and guidance for surveillance and treatment strategies are lacking.

Aim

To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behaviour and outcomes of malignant OANs.

Methods

A retrospective clinicopathological review of 10 histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas. We reviewed all the cases of malignant OAN reported in the literature and compared to our case series.

Results

Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin–Weiss–Bisceglia criteria, LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1.

Conclusion

In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signalling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.

Abstract

Background

Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behaviour compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours, and guidance for surveillance and treatment strategies are lacking.

Aim

To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behaviour and outcomes of malignant OANs.

Methods

A retrospective clinicopathological review of 10 histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas. We reviewed all the cases of malignant OAN reported in the literature and compared to our case series.

Results

Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin–Weiss–Bisceglia criteria, LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1.

Conclusion

In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signalling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.

Introduction

Oncocytic adrenocortical neoplasm (OAN) represents a histological variant of adrenocortical neoplasm, consisting predominantly or exclusively of epithelial cells with abundant granular eosinophilic cytoplasm. The first adrenal oncocytoma was discovered in 1986 (Kakimoto et al. 1986), and since then, more than 150 cases have been reported in the literature (Peynirci et al. 2018).

Malignant OAN is reported to have a more favourable outcome with a superior 5-year survival rate compared to conventional ACC (Wong et al. 2011). Current prognostic scoring systems appear to overestimate the malignancy potential of OANs. The Weiss scoring system, which is widely used to distinguish benign from malignant adrenocortical neoplasms, cannot be applied to OAN, but three of the nine scoring criteria are intrinsic to OAN biology: high nuclear grade (<25% clear cells and diffuse architecture) (Bisceglia et al. 2004), automatically designating all OANs as malignant. The Lin–Weiss–Bisceglia (LWB) criteria, recommended by the 2017 WHO update on endocrine tumours (Lam 2017), categorizes an OAN as malignant if the tumour fulfils any of the following major criteria: mitotic rate >5 mitoses per 50 hpf, any atypical mitoses, any venous invasion or as borderline if the tumour exhibits any of the minor criteria: large size >10 cm and/or >200 g, necrosis, capsular invasion or sinusoidal invasion and benign if no major or minor criteria are fulfilled. Of recent interest, the Ki-67 proliferation index and the Helsinki score, a combination of morphological parameters (presence of necrosis and mitotic count >5 per 50 hpf) and Ki-67 index appear to be a more specific predictor of survival and poor outcome in malignant OAN (Duregon et al. 2017, Renaudin et al. 2018).

Molecular profiling provides key prognostic information in other endocrine tumours, and genetic profiling of adult-onset ACC has been investigated with the majority of cases occurring sporadically. However, cases have been identified associated with germline mutations in the mismatch repair genes MSH6 and MSH2 that cause Lynch syndrome (Raymond et al. 2013, Zheng et al. 2016, Casey et al. 2018). Additionally, a small subset of adult ACC cases (1–2%) is associated with mutations in multiple endocrine neoplasia type 1 gene MEN1 (Else et al. 2014). Molecular and genetic studies of ACC have highlighted a number of key molecular predictors of oncogenic progression including TP53, insulin-like growth factor 2 (IGF2), multiple endocrine neoplasia type 1 (MEN1) and β-catenin (CTNNB1) (Giordano et al. 2003, Tissier et al. 2005, Zheng et al. 2016). Few molecular studies have included OAN, and therefore, little is known about the molecular profile of OAN compared to ACC.

The aims of this study were to describe and identify clinical, molecular and histopathologic markers of malignant vs benign OAN in our case series and in the literature in order to identify key prognostic markers, which may facilitate a stratified management approach for patients with OAN.

Methods

Clinical data

Data on 10 histologically confirmed OANs from an electronic hospital database in Cambridge University Hospitals NHS Trust, UK, from 2001 to 2018 were retrospectively reviewed. The secretory status of these adrenal tumours was guided by a standardised hospital-based biochemistry protocol consisting of plasma/urinary metanephrines, overnight dexamethasone suppression test/salivary cortisol/24 h urinary cortisol, ACTH, DHEAS, plasma aldosterone concentration and plasma renin activity.

Adrenal lesions were characterised as benign on CT if the Hounsfield unit (HU) on plain imaging was <10, absolute washout >60% or relative washout >40% or low signal intensity on out-of-phase signal images on MRI and indeterminate if these criteria were not fulfilled. Clinicopathological information including association with other malignancy, type of surgery, European Network for the Study of Adrenal Tumors (ENSAT) stage, treatment regimen and clinical outcome data were collected. Informed consent was obtained on all patients (IRAS ID 133065).

Histopathological review

Histopathological examination was conducted by a single experienced pathologist with a special interest in endocrine pathology (AM). Tumour size, resection margins and tumour category were determined. R0 resection was defined as the absence of macroscopic or microscopic extension of the tumour at the surgical margin, while R1 resection was defined as the presence of microscopic extension of the tumour along the line of resection. Prognostic scoring systems including the Weiss and modified Weiss scores, LWB scores, Helsinki scores and Ki-67 proliferative index were recorded.

Tumour immunohistochemistry

Immunohistochemical staining was performed with monoclonal mouse anti-human Ki-67 antibody (clone MIB-1, M7240; dilution 1:100; Agilent Technologies) in a Leica BOND-III IHC autostainer, with antigen retrieval performed at pH 9.0 by using a Leica Epitope retrieval solution 2 for 20 min at 100°C. Slides were counterstained with haematoxylin (Leica Biosystems) and mounted with ClearVue mounting medium (Thermo Fisher Scientific).

Ki-67 analysis was evaluated using manual analysis (MA) of 'hot spots' (Yamazaki et al. 2016). Hot spots, which contained the most frequent Ki-67-positive cells, were selected through scanning the whole immunostained slide preparation. MA was performed using the ×40 microscope objective of 1000 cells in hot spot areas. The Ventana Benchmark mismatch repair panel (MSH2 (G219-1129) and CONFIRM anti-MSH6) was performed on 4-µm sections of paraffin-embedded tumour tissue in accordance with the manufacturer’s guidelines and interpreted by an experienced pathologist (AM).

Germline and tumour whole exome sequencing

Germline DNA was collected from four patients with OANs and five patients with ACC. Tumour DNA was analysed for four OAN cases and four ACC cases sequenced in house and reviewed alongside data available from The Cancer Genome Atlas (TCGA) for OANs (four cases) and ACC (86 cases). Germline DNA was extracted from blood. Tumour tissue was microdissected from formalin-fixed paraffin-embedded blocks, and DNA was extracted using a Covaris ultrasonicator. For all individuals, DNA was extracted from blood and prepared for PE125 whole exome sequencing (WES) using the Nextera Rapid Capture Exome enrichment kit (Illumina). Sequencing was performed on HiSeq-4000 machines and analysed with a standard in-house pipeline following GATK best practice recommendations for WES data (Supplementary material, see section on supplementary materials given at the end of this article). Germline TCGA data were downloaded in BAM format and reprocessed using the same WES pipeline (Supplementary material).

Germline variant prioritisation and candidate selection

Germline sequencing data from all samples were analysed to identify any known cancer-predisposing variants. Common variants that appeared in greater than 1% of the non-Finnish European 1000 genomes population were removed from analysis. Protein-affecting variants (loss of function, inframe insertions and deletions and predicted deleterious and probably damaging missenses (as flagged by SIFT and PolyPhen respectively) were selected for further analysis. Variants that passed filtering were manually examined and prioritised to select candidates.

Tumour variant analysis

A full set of somatic variants was generated for all nine tumour samples. Variants were filtered to select those with a variant allele frequency of greater than 10%. For each sample, tumour mutation burden was calculated. Hypermutated samples were defined as those with a mutation burden of greater than 10 mutations/Mb. Somatic variants were explored to identify any known links to tumour development. Copy number variants were assessed using CNVkit (Talevich et al. 2016), which was run in batch mode on matched tumour and normal samples.

Samples from TCGA were analysed in a separate batch to account for differences in exome capture and sequencing. The Log2 copy number ratio was assessed across binned regions for each matched pair and plotted to identify copy number changes. A gain of a single copy of a genomic region was defined by a log2 copy number ratio of 0.5, and a loss of a single copy was defined by a log2 copy number ratio of –1 (±25%) according to CNVkit protocol (Talevich et al. 2016). Metrics were calculated on copy number calls to filter out the false positives with a s.e. of greater than 0.01.

Tumour mutational signatures

Tumour mutational signatures were calculated to identify any overlapping oncogenic drivers of ACC and OAN development. The deconstruct Sigs package for R was used to assess the pattern of somatic single nucleotide variants and assign to each sample the top COSMIC oncogenic signatures.

Literature review

A comprehensive literature search was performed via PubMed using the MeSH terms 'adrenal or adrenocortical or adrenal gland' and 'oncocytic' and 'neoplasm or carcinoma or tumour' to retrieve all published full articles and abstracts related to OAN in English. Data extracted from the reports included age, gender, presentation, functionality, site, size and weight, prognostic scoring systems, Ki-67 proliferative index, treatment and clinical outcomes.

Statistical analysis

Categorical variables were expressed as numbers (n) and percentages (%), and continuous variables were expressed as mean ± s.d. or median (minimum–maximum) if non-parametric. Data were analysed using SPSS version 23.0.

Results

Clinical features

The clinical characteristics of 10 OAN cases identified from our database are summarised in Table 1. According to the LWB criteria, eight cases were classified as malignant, one borderline and one benign. In the malignant category, six were males and two were females with a mean age of 60 ± 11 years. Three of eight cases were secretory adrenal tumours, of which two were cortisol secreting and the third was deoxycorticosterone secreting. Both cases in the borderline and benign category were cortisol secreting. Five of eight malignant OAN and one borderline OAN were characterised as indeterminate on imaging. The malignant OANs were larger with a mean maximum diameter of 120.7 ± 52.0 mm compared to the borderline (68 mm) and benign (20 mm) cases, respectively. Two patients with malignant OAN had a history of a second primary tumour, case 3 with a molecularly confirmed diagnosis of Lynch syndrome previously published by our group (Challis et al. 2016), and case 4 had a history of a metastatic well-differentiated neuroendocrine tumour of unknown primary. Finally, case 10 with a benign adrenal oncocytoma also had a history of a well-differentiated mid-gut neuroendocrine tumour.

Table 1

Clinical features and treatment of 10 oncocytic adrenocortical neoplasms prognosticated according to the LWB criteria system.

Case 1aCase 2Case 3Case 4Case 5Case 6Case 7Case 8Case 9aCase 10
LWB criteriaMalignantMalignantMalignantMalignantMalignantMalignantMalignantMalignantBorderlineBenign
Age (years)66435571587271465964
SexMMFMMMMFFF
Presenting featureIncidentalAbdominal massIncidentalIncidentalCushing’s syndrome, hypogonadismHypokalemia and proximal myopathyIncidentalIncidentalIncidentalIncidental
Other malignanciesNilNilOvarian carcinoma and a malignant colorectal polypMetastatic NETNilNilNilNilNilMetastatic NET
Excess hormoneCortisolNilNilNilCortisolDeoxycorticosteroneNilNilCortisolCortisol
SiteLeftLeftRightRightLeftRightLeftRightLeftLeft
Max diameter (mm)10520513010513578381706820
Imaging characterizationN/AN/AN/AIndeterminateIndeterminateIndeterminateIndeterminateIndeterminateIndeterminateBenign
Type of surgeryLaparoscopicOpen and splenectomyOpen and nephrectomyOpen and liver resectionLaparoscopicOpenLaparoscopicOpenLaparoscopicOpen
Weight (g)3281893927N/A21424063.59686023
Adjuvant treatmentMitotane + EDPMitotane + RT+ EDPMitotaneNilMitotaneNilNilNilNilNil

aReferred postoperatively to our centre.

EDP, etoposide, doxorubicin, carboplatin; NET, Neuroendocrine tumour; RT, radiotherapy.

Immunohistopathological review

The histological findings are summarised in Table 2. All cases in the malignant group had a Weiss and modified Weiss score of >3 compared to the borderline/benign group with scores of <3. Seven out of eight malignant OAN cases were pure oncocytic tumours (composed of at least 90% oncocytes). All but one case (case 4) in the malignant category of OANs were classified as ENSAT stage 3 or above at presentation compared to the borderline/benign OAN group, which were classified as ENSAT stage 2. The malignant OANs had a median Ki-67 proliferative index of 16.45% (range: 3–53%) and median Helsinki score of 22.1 (range: 8–61.3) greater than that of the borderline (Ki-67 proliferative index 1.3 and Helsinki score 1.3) and benign (Ki-67 proliferative index 2.1 and Helsinki score 2.1) cases. The three malignant OAN cases with poorer outcomes (cases 1, 2, 5) had a greater average Ki-67 proliferative index of 27.9 and Helsinki score of 34.9 when compared to the five cases with better outcomes (Ki-67 proliferative index of 13.4 and Helsinki score 18 but were not statistically significant, P = 0.215, P = 0.161). MSH2 and MSH6 staining were absent in case 3 and a similar staining pattern was identified in the OAN from case 2, although no pathogenic germline or somatic variant in a mismatch repair gene was identified.

Table 2

Immunohistopathological features and outcome of 10 oncocytic adrenocortical neoplasm.

Case 1aCase 2Case 3Case 4Case 5Case 6Case 7Case 8Case 9aCase 10
Weiss criteria8766663621
Modified Weiss criteria7554763412
LWB criteriaMalignantMalignantMalignantMalignantMalignantMalignantMalignantMalignantBorderlineBenign
CategoryPurePurePurePureMixedPurePurePureMixedN/A
Resection marginR1R1R0R0R1R0R0R0R1R0
Ki-67 (%)13.516.917.48.253.31622.831.32.1
Helsinki score21.521.922.413.261.32422.981.32.1
ENSAT stage333233222N/A
MSH 2PreservedAbsentAbsentPreservedPreservedPreservedPreservedPreservedPreservedN/A
MSH 6PreservedAbsentAbsentPreservedPreservedPreservedPreservedPreservedPreservedN/A
Recurrence/metastasesRecurrence locally, peritoneum and rectumBone metastasesNilNilRecurrence locally & peritoneumNilNilNilNilNil
OutcomeDOD at 24 monthsAED at 82 monthsANED at 232 monthsANED at 87 monthsAED 38 monthsANED at 25 monthsANED at 43 monthsANED at 60 monthsANED at 32 monthsANED at 96 months

aReferred postoperatively to our centre.

AED, alive with evidence of disease; ANED, alive with no evidence of disease; DOD, dead of disease.

Disease outcomes

All individuals with malignant OAN cases had adrenalectomy, three laparoscopically and five open, achieving R0 resection in a third laparoscopically and 80% open. The three cases with R1 resection margins (two laparoscopic adrenalectomy and one open adrenalectomy) had poor outcomes including one death following tumour recurrence (case 1) and two cases with metastases or recurrence with residual disease (cases 2 and 5). The median follow-up was 51.5 (range: 24–232) months. The five remaining individuals with malignant OAN remain free of disease with follow-up period from 25 to 232 months (Table 1).

Germline whole exome sequencing analysis

A germline, loss of function, splice donor variant (NM_000179.2:c.3438+1G>A, rs267608096) in the Lynch syndrome gene MSH6 was identified in one affected female (case 3). Immunohistochemistry studies on available tumour showed a loss of mismatch repair proteins MSH2 and MSH6. This variant has previously been described by our group and has been labelled as a ‘likely pathogenic’ Lynch syndrome variant (ClinVar submission accession: SCV000108066.2). Immunohistochemistry of the tumour from a second individual with OAN (case 2) also demonstrated loss of MSH2 and MSH6 expression; however, no germline predicted pathogenic variants in the Lynch syndrome genes were identified.

Comparing the results of the germline sequencing data from the OAN group with the five cases of conventional ACC, a second pathogenic germline Lynch syndrome-associated variant was identified in a female in the conventional ACC group (ACC6), which has also previously been published by our group (Casey et al. 2018) (Table 3). This was a frameshift deletion (NM_000251:c.787delA) in MSH2 which was consistent with the loss of MSH2 and MSH6 expression seen in the tumour and a medical history consistent with Lynch syndrome (Casey et al. 2018). Reviewing the TCGA-ACC dataset, no pathogenic or likely pathogenic variants in MSH2, MSH6 or MSH3 were identified. However, predicted deleterious and damaging missense variants were found in mismatch repair genes MLH1 and PMS2. A missense variant in MLH1 (NM_000249.2c.1853A>C) was found in two individuals, both with conventional ACC. The missense variant in PMS2 (NM_000535.7:c.903G>T) was reported as 'Likely Pathogenic' by ClinSig and was found in one individual with conventional ACC.

Table 3

Malignant oncocytic adrenocortical neoplasms: review of the literature and clinicopathologic data and outcomes.

Total casesAuthor, yearNAgeGenderPresentationFunctionalitySiteSize (mm)Weight (g)CategoryMibiRecurrence/metastasesOutcomeMitotaneChemotherapy/radiotherapy
1(el-Naggar et al. 1991)156MAbdominal painNoR80N/AN/AN/AN/AN/AYesRadiotherapy
2(Kurek et al. 2001)174FIncidentalNoLN/AN/AN/AN/ARecurrence (local) and metastases (Ovarian)AEDNoNo
6(Hoang et al. 2002)139MAscites, abdominal painNoL140N/AN/AN/AN/AANEDNoNo
253FAbdominal painNoL1701200N/AN/AMetastases (bone and lung)AEDNoNo
358MAbdominal massNoR130740N/AN/ANoANEDNoNo
471MAbdominal massNoL85100N/AN/ANoANEDNoNo
7(Tanaka et al. 2004)154MAbdominal massSubclinical CSRN/AN/AN/AN/AMetastases (Bone, lung, liver, contralateral adrenal)AEDYesNo
8(Seo et al. 2002)149FIncidentalNoL85N/AN/AN/ARecurrence (Intrabdominal carcinomatosis)DODNoNo
12(Song et al. 2004)164FIncidentalNoL110420N/A<1NoANEDNoNo
247FAbdominal painNoL1501220N/A<1Recurrence and metastases (retroperitoneal mass and celiac lymph node)ANEDNoNo
337FAbdominal painNoL115410N/A<1NoANEDNoNo
435MIncidentalNoR85290N/A<1NoANEDNoNo
16(Bisceglia et al. 2004)146MGynecomastiaNoR1701900N/A5–20RecurrenceDODN/AN/A
232FIncidentalSubclinical CSR1102520N/A2–15RecurrenceAEDN/AN/A
362FIncidentalNoR80260N/A5NoDNODN/AN/A
477FIncidentalNoL100120N/A5–20NoANEDN/AN/A
17(Ali & Raphael 2007)125MHypokalemiaCortisol and aldosterone secretingR8590N/A10Recurrence (local and hepatic invasion)AEDN/AN/A
18(Ohtake et al. 2010)169MAbdominal painNoL75N/AN/A5.9N/AN/AN/AN/A
19(Argyriou et al. 2008)154MLung massNoRN/AN/AN/A10–20Recurrence and metastases (lung and bone)DODYesChemotherapy
20(Juliano et al. 2008)145FAbdominal painAndrogen excessR110410N/AN/ARecurrence and metastases (bone, liver, lung)AEDNoChemotherapy & radiotherapy
21(Mwandila et al. 2010) (Abstract)119FHirsutism, acne, oligomenorrheaAndrogen excessL50N/AN/AN/AN/AN/AN/AN/A
29(Wong et al. 2011)153FVirilizingAndrogen excessL130670Pure5Recurrence and metastasesAEDN/AN/A
236FIncidentalNoL145885Pure30N/ADODN/AN/A
369FIncidentalNoL6076Pure2N/AN/AN/AN/A
447FIncidentalAndrogen excessL105552Pure30N/ADODN/AN/A
536MCSCortisol excessR80155Pure10N/AANEDN/AN/A
641FVirilizingAndrogen excessL2855720Pure6Metastases (liver)AEDN/AN/A
768FIncidentalCortisol excessR8070Pure30RecurrenceDODN/AN/A
829MGynecomastiaEstrogen/prolactin excessL2001120Pure10RecurrenceAEDN/AN/A
41(Duregon et al. 2011)131FN/ANoL95255PureN/AN/AANEDN/AN/A
260MN/ANoL168PureN/AN/AANEDN/AN/A
368FN/ANoR170N/APureN/AN/AANEDN/AN/A
466FN/ANoN/AN/AN/APureN/AN/AANEDN/AN/A
546MN/ANoL180950PureN/AN/AANEDN/AN/A
632MN/ANoR230N/APureN/AN/ADODN/AN/A
744FN/ACortisol excessR80N/AMixedN/AN/ADODN/AN/A
835MN/ANoL8040MixedN/AN/AANEDN/AN/A
967FN/ACortisol excessL1501050MixedN/AN/AANEDN/AN/A
1044MN/ACortisol excessR2001300MixedN/AN/ADODN/AN/A
1146FN/ANoL99270MixedN/AN/AANEDN/AN/A
1228MN/ACortisol excessL110210MixedN/AN/ADODN/AN/A
42(Kalra et al. 2015)134MIncidentalNoL160N/AN/AN/ANoANEDN/AN/A
43(Carré et al. 2016)150FVirilizingAndrogenL35N/AN/A6.8NoANEDN/AN/A
44(Sumner et al. 2017) (Abstract)183FIncidentalNoN/AN/AN/AN/AN/AN/AN/AN/A
45(Panizzo et al. 2018)148MIncidentalNoL123300N/A20NoANEDNoN/A
46(Al Balooshi et al. 2018)137MIncidentalCortisolLN/AN/AN/AN/AN/AN/AN/A
80(Renaudin et al. 2018)3450 (42–57)19 F (55%)Incidental 16 (47%)17 (54%)24 L (70%)83 (60–126)200 (80–500)2/3 purePoor outcome (n = 3)

12

Good outcome (n = 23)

3
3 Recurrence2 died

1 AED
18 (55%)4 (Radiotherapy)

AED, alive with evidence of disease; ANED, alive with no evidence of disease; DOD, dead of disease.

Tumour whole exome sequencing analysis

Whole exome sequencing of DNA extracted from tumour was performed for two OAN samples and analysed in conjunction with sequence data from four OAN samples from the TCGA cohort and compared to three ACC tumour samples sequenced in house. In total, 2325 somatic variants were called across the set (542 synonymous, 1783 non-synonymous); 78% of these (1828 variants) were found in two hypermutated tumours, one oncocytic and one conventional ACC tumour. One of these hypermutated tumours with a mutation burden of 14.97 mutations/Mb was from case 3 with a pathogenic germline MSH6 variant. This is consistent with previous evidence that Lynch-driven ACCs have a higher mutation burden than non-Lynch tumours (Zheng et al. 2016). The average mutation burden in this cohort was 6.35 mutations/Mb and was markedly higher for in-house sequenced OAN samples (10.67 mutations/Mb) than for the included OAN TCGA samples (0.95 mutations/Mb). On average, the ACC samples had a higher mutation burden than the OAN samples (usual type ACC: 11.72 mutations/Mb, OAN: 3.67 mutations/Mb) although these results are largely driven by the presence of the two hypermutated samples. Of the non-hypermutated samples, the average mutation burden was 1.70 mutations/Mb and was comparable between ACC and OAN samples (ACC: 2.45 mutations/Mb, OAN: 1.41 mutations/Mb).

A frameshift deletion in ATM (NM_000051:c.1875delT) (VAF 41.0%) and a pathogenic missense variant in TP53 (NM_000546.5:c.524G>A, rs28934578) (VAF 27.9%) were identified in the OAN from case 3 (Table 3). Other notable findings in this tumour included missense variants in NFKB2, NF2 and USP6. We also identified a pathogenic missense variant in CTNNB1 in the OAN of case 1 with a VAF of 42.6%.

Of the four OAN tumour samples from TCGA, a somatic pathogenic mutation within a driver gene was found in only one sample. An OAN carried a somatic PIK3CA missense variant (NM_006218.2:c.3140A>G, rs121913279) with a VAF of 21.0% (Table 4). This OAN had the highest mutation burden of the tested TCGA samples with 1.51 mutations/Mb.

Table 4

Pathogenic Germline candidate variants identified in cases with OAN and compared to ACC cases and TCGA-ACCA data set.

CaseSexTumour typeTumour tissue sequencedMutations per megabase in tumourGermline variant
Case 1MaleOANYes3.243979NA
Case 2MaleOANNoNANA
Case 3FemaleOANYes14.96623MSH6:NM_000179.2:c.3438+1G>A
Case 7MaleOANNoNANA
Case 8FemaleOANNoNANA
ACC1FemaleACCYes2.637655NA
ACC2MaleACCYes2.26337NA
ACC3FemaleACCNoNANA
ACC4MaleACCNoNANA
ACC 5FemaleACCYes30.26555NA
ACC6FemaleACCNoNAMSH2:NM_000251:c.787delA
TCGA_OR_A5JDFemaleOANYes0.981044NA
TCGA_OR_A5JHFemaleOANYes0.424729NA
TCGA_OR_A5K3MaleOANYes0.886876NA
TCGA_OR_A5LKMaleOANYes1.509795NA

Somatic copy number alterations were noted in one OAN sample (case 1) compared to three conventional ACC samples. Finally, mutation signature analysis was performed to identify the predominant mutational processes enacting on these tumours. COSMIC signature 1 was the most commonly occurring signature across all samples. The presence of this signature correlates with age and occurs in most cancer samples according to the COSMIC-predicted aetiology (Alexandrov et al. 2013). There was no evidence of a difference in mutational signatures between OAN and conventional type ACC samples in this study.

Literature review

Eighty malignant OAN cases described in 18 full English articles and two abstracts were reviewed and detailed in Table 5. Malignant OANs occur at a mean age of 49 ± 15 years with a female predilection in a 1.2:1 ratio. The neoplasms were large with a mean maximum diameter of 117.7 mm ± 53.4 mm. From the available data, 45% of tumours were secretory; 42.8% of malignant OANs were treated with mitotane, 10.4% with radiotherapy and 2% with chemotherapy alone or in combination with radiotherapy. A total of 16.2% of patients died as direct cause of their OAN, 13.5% of patients were alive with residual disease from either recurrence or metastases and 68.9% were disease free and well. The most common site of recurrence/metastases was bone, lungs, liver, adrenal bed, peritoneum, ovary and contralateral adrenal gland. The clinical and pathological data and outcomes were compared to our case series detailed in Supplementary Table 1.

Table 5

Somatic variants identified in ACC tumours. Oncocytic ACCs are indicated with *.

GeneTranscript IDVariantIDConsequenceSampleVariant allele frequency
APCNM_000038c.4718delACOSM267970Frameshift variantACC10.78
ATMNM_000051c.1875delTCOSM1350784Frameshift variantCase 3*0.41
CTNNB1NM_001330729.2c.113C>Trs121913407Missense variantCase 1 and ACC2ACC1:0.43, ACC4:0.42
MSH6NM_000179c.846delGNAFrameshift variantACC20.17
NF2NM_000268c.1231C>Trs773296925Missense variantCase 3*0.29
NFKB2NM_001077494c.2369G>ANAMissense variantCase 3*0.22
PIK3CANM_006218.2c.3140A>Grs121913279Missense variantTCGA_OR_A5LK*0.21
TP53NM_000546.5c.524C>Trs28934578Missense variantCase 3*0.28
TP53BP1NM_005657c.4339G>ACOSM961975Stop gainedACC50.14
USP6NM_004505c.2197C>TNAMissense variantCase 3*0.34

Discussion

OANs are rare tumours with an indolent nature conferring a superior clinical outcome and survival rate compared to conventional ACC. Estimated overall median survival for malignant OAN is 58 months compared to conventional ACC, which is 14–32 months (Wong et al. 2011), and survival at 2 years for malignant OAN surpasses 92% compared to 61% in conventional ACC (Renaudin et al. 2018).

A complete, margin-free surgical resection is crucial in determining positive clinical outcomes for ACC and malignant OANs. Achieving R0 resection in adrenocortical carcinoma compared to R1 resection improved 5-year overall survival rates (64.8% vs 33.8%, P < 0.001) and 5-year recurrence-free survival rates (30.3% vs 13.8%, P = 0.03) with surgical margin status as an independent predictor of poor overall survival (Margonis et al. 2016). The three malignant OANs (two laparoscopic adrenalectomy and one open adrenalectomy) with poor outcomes resulting in one death and two metastatic recurrence in our series had a R1 resection margin (Table 1). Although data on resection margins for malignant OAN described in case reports/series were scarce, Renaudin et al. reported that all 43 malignant OANs in their series underwent complete surgical treatment with R0 resection and only three poor outcomes ensued: two deaths and one alive with relapse (Renaudin et al. 2018). In a recent review, the surgical approach to adrenal cancers (ENSAT I-III) either by laparoscopic or open adrenalectomy confers similar R0 resection rates, overall recurrence, disease free and overall survival rates implying that the adequacy of tumour resection is pivotal rather than the surgical approach (Mpaili et al. 2018).

Four cases of malignant OANs in our series were treated with mitotane achieving therapeutic mitotane levels comparable with the literature with almost half of malignant OAN cases treated with mitotane. The overall survival in the mitotane-treated malignant OAN (in comparison to the mitotane-treated conventional ACC group) was better, possibly due to the unique biological behaviour of OAN (Renaudin et al. 2018). Experience with other treatment modalities such as chemotherapy and radiotherapy in our series and in the literature is limited.

Following the recommendation by the WHO of endocrine tumours (Lam 2017), we classified our cohort according to the LWB score into malignant, borderline and benign category, and we also applied the Helsinki score and reviewed the proliferation indices. Our cases from the borderline and benign category of OANs had low proliferation indices <5% and the remaining malignant cases except one (case 8: 3%) had indices >5% (Table 2). Bisceglia et al. documented that a proliferation index of ≥5% correlated well with mitotic activity in all malignant cases including recurrences for both ACC and OANs, except in a single case with a value <2%, and all benign tumours in this study had a proliferation index <5% (range 0–4%) (Bisceglia et al. 2004).

The Helsinki score, consisting of a combined assessment of morphological indices (mitotic count >5 per hpf and presence of necrosis) and Ki-67 proliferation index, appears to be the most specific in predicting the clinical outcome of malignant OAN. Initially introduced as a prognostic assessment system for ACC, a score of 8.5 was able to identify metastatic ACC (Pennanen et al. 2015), and in a more recent paper, a Helsinki score >8.5 appears to be most discriminative in identifying aggressive malignant OAN with a better specificity compared to the LWB score, Weiss score and reticulin algorithm (Renaudin et al. 2018). Seven out of eight cases in our malignant OAN series had a Helsinki score of >8.5, including the three cases for whom poor outcomes were recorded with scores of 21.5, 21.9 and 61.3, respectively. The two cases in the borderline and benign category had low scores of 1.3 and 2.1, respectively. Although Ki-67 proliferative index incorporated into the Helsinki score may play a role in predicting poorer outcomes, the presence of necrosis, another variable in the score, was the only histological difference between malignant OAN with poor outcomes vs those with good outcomes in the largest series of malignant OAN to date (Renaudin et al. 2018). In this smaller study, necrosis was identified at histological review in five malignant OANs from patients who have had a good outcome to date with no evidence of disease recurrence or metastases at a median of 60 months post-surgery.

Germline and somatic pathogenic variants were identified in MSH2 and MSH6, further highlighting the role of mismatch repair genes in both conventional ACC and OANs. An additional case with a malignant OAN in this series (case 2) had evidence of mismatch repair deficiency on immunohistochemistry (loss of MSH2 and MSH6 expression) but no pathogenic germline or somatic variant was identified. The OAN from case 3 was found to be hypermutated and also had heterozygous somatic variants in DNA repair and checkpoint genes TP53 and ATM, which potentially contributed to the hypermutation phenotype.

Neither of the main oncogenic events identified in this study, including DNA repair deficiency and dysregulation of Wnt signalling by β-catenin, were specific to usual-type or oncocytic-type ACCs. Patients with both tumour types had a comparable age of onset and were equally affected by germline predisposing variants in mismatch repair genes. Similarly, there was little difference in mutation burden of both tumour types, and no defining mutation signatures that could be attributed to each group were identified. This suggests that the oncocytic subtype of ACC is genetically similar to conventional ACC in both predisposing and oncogenic mechanisms. It seems likely that OANs will have similar molecular drivers to those described by the TCGA-ACC study (Zheng et al. 2016).

Limitations to this study include the retrospective design and small study number, but the study was enriched through inclusion of an up-to-date literature review and by comparing sequencing data from this series to data available in TCGA.

In summary, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN in this series. A proliferation index >5% and Helsinki score >8 also predicted poorer outcomes for malignant OANs in this series, and these scores may aid in stratifying the management of OANs in clinical practice. Ensuring a complete, margin-free resection is crucial in improving overall prognosis and survival. Finally, molecular profiling identified dysregulation in DNA repair and Wnt signalling pathways in both OAN and ACC samples, suggesting a shared molecular overlap between OAN and conventional ACC.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EO-21-0011.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

Dr Casey is funded by GIST Support UK. This work has been funded and supported by the UK Medical Research Council/Sackler programme (E F), the European Union Seventh Framework Program (2007–2013)/European Research Council (310018) (M T).

Author contribution statement

E F, S K, R C, B C, V K, M T, O G, A S, A L, G R C and A M were involved in study design and concept and drafting and review of the final manuscript. E F, S K, R C, G R C and A M were involved in data collection and analysis and E F, S K, M T, B C, A M, A S, V K and A L contributed to the final review of data included.

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  • Al Balooshi B, Miyanath S, Elhennawy A, Saeedi Y, Tirmazy SH, Muhasin M, Ray B, Al Sharhan M, Hotait H & Houcinat Y et al. 2018 Adrenocortical oncocytic carcinoma and papillary thyroid carcinoma incidentally detected in an asymptomatic patient by F-18 FDG PET/CT. Asia Oceania Journal of Nuclear Medicine and Biology 6 179185. (https://doi.org/10.22038/aojnmb.2018.10845)

    • Search Google Scholar
    • Export Citation
  • Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A & Børresen-Dale AL et al. 2013 Signatures of mutational processes in human cancer. Nature 500 415421. (https://doi.org/10.1038/nature12477)

    • Search Google Scholar
    • Export Citation
  • Ali AE & Raphael SJ 2007 Functional oncocytic adrenocortical carcinoma. Endocrine Pathology 18 187189. (https://doi.org/10.1007/s12022-007-9000-4)

    • Search Google Scholar
    • Export Citation
  • Argyriou P, Zisis C, Alevizopoulos N, Kefaloyannis EM, Gennatas C & Petraki CD 2008 Adrenocortical oncocytic carcinoma with recurrent metastases: a case report and review of the literature. World Journal of Surgical Oncology 6 134. (https://doi.org/10.1186/1477-7819-6-134)

    • Search Google Scholar
    • Export Citation
  • Bisceglia M, Ludovico O, Di Mattia A, Ben-Dor D, Sandbank J, Pasquinelli G, Lau SK & Weiss LM 2004 Adrenocortical oncocytic tumors: report of 10 cases and review of the literature. International Journal of Surgical Pathology 12 231243. (https://doi.org/10.1177/106689690401200304)

    • Search Google Scholar
    • Export Citation
  • Carré J, Grunenwald S, Vezzosi D, Mazerolles C, Bennet A, Meduri G & Caron P 2016 Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies. Gynecological Endocrinology 32 662666. (https://doi.org/10.3109/09513590.2016.1149811)

    • Search Google Scholar
    • Export Citation
  • Casey RT, Giger O, Seetho I, Marker A, Pitfield D, Boyle LH, Gurnell M, Shaw A, Tischkowitz M & Maher ER et al. 2018 Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab. Seminars in Oncology 45 151155. (https://doi.org/10.1053/j.seminoncol.2018.06.001)

    • Search Google Scholar
    • Export Citation
  • Challis BG, Kandasamy N, Powlson AS, Koulouri O, Annamalai AK, Happerfield L, Marker AJ, Arends MJ, Nik-Zainal S & Gurnell M 2016 Familial adrenocortical carcinoma in association with Lynch syndrome. Journal of Clinical Endocrinology and Metabolism 101 22692272. (https://doi.org/10.1210/jc.2016-1460)

    • Search Google Scholar
    • Export Citation
  • Duregon E, Volante M, Cappia S, Cuccurullo A, Bisceglia M, Wong DD, Spagnolo DV, Szpak-Ulczok S, Bollito E & Daffara F et al. 2011 Oncocytic adrenocortical tumors: diagnostic algorithm and mitochondrial DNA profile in 27 cases. American Journal of Surgical Pathology 35 18821893. (https://doi.org/10.1097/PAS.0b013e31822da401)

    • Search Google Scholar
    • Export Citation
  • Duregon E, Cappellesso R, Maffeis V, Zaggia B, Ventura L, Berruti A, Terzolo M, Fassina A, Volante M & Papotti M 2017 Validation of the prognostic role of the ‘Helsinki Score’ in 225 cases of adrenocortical carcinoma. Human Pathology 62 17. (https://doi.org/10.1016/j.humpath.2016.09.035)

    • Search Google Scholar
    • Export Citation
  • el-Naggar AK, Evans DB & Mackay B 1991 Oncocytic adrenal cortical carcinoma. Ultrastructural Pathology 15 549556. (https://doi.org/10.3109/01913129109016262)

    • Search Google Scholar
    • Export Citation
  • Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ & Hammer GD 2014 Adrenocortical carcinoma. Endocrine Reviews 35 282326. (https://doi.org/10.1210/er.2013-1029)

    • Search Google Scholar
    • Export Citation
  • Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, Sanders D, Aljundi RT, Gauger PG & Thompson NW et al. 2003 Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. American Journal of Pathology 162 521531. (https://doi.org/10.1016/S0002-9440(1063846-1)

    • Search Google Scholar
    • Export Citation
  • Hoang MP, Ayala AG & Albores-Saavedra J 2002 Oncocytic adrenocortical carcinoma: a morphologic, immunohistochemical and ultrastructural study of four cases. Modern Pathology 15 973978. (https://doi.org/10.1038/modpathol.3880638)

    • Search Google Scholar
    • Export Citation
  • Juliano JJ, Cody RL & Suh JH 2008 Metastatic adrenocortical oncocytoma: a case report. Urologic Oncology 26 198201. (https://doi.org/10.1016/j.urolonc.2007.02.008)

    • Search Google Scholar
    • Export Citation
  • Kakimoto S, Yushita Y, Sanefuji T, Kondo A, Fujishima N, Kishikawa M & Matsumoto K 1986 Non-hormonal adrenocortical adenoma with oncocytoma-like appearances. Hinyokika Kiyo: Acta Urologica Japonica 32 757763.

    • Search Google Scholar
    • Export Citation
  • Kalra S, Manikandan R & Srinivas BH 2015 Oncocytic adrenocortical carcinoma-a rare pathological variant. BMJ Case Reports 2015 14. (https://doi.org/10.1136/bcr-2014-208818)

    • Search Google Scholar
    • Export Citation
  • Kurek R, Von Knobloch R, Feek U, Heidenreich A & Hofmann R 2001 Local recurrence of an oncocytic adrenocortical carcinoma with ovary metastasis. Journal of Urology 166 985. (https://doi.org/10.1016/S0022-5347(0565882-X)

    • Search Google Scholar
    • Export Citation
  • Lam AK 2017 Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocrine Pathology 28 213227. (https://doi.org/10.1007/s12022-017-9484-5)

    • Search Google Scholar
    • Export Citation
  • Margonis GA, Kim Y, Prescott JD, Tran TB, Postlewait LM, Maithel SK, Wang TS, Evans DB, Hatzaras I & Shenoy R et al. 2016 Adrenocortical carcinoma: impact of surgical margin status on long-term outcomes. Annals of Surgical Oncology 23 134141. (https://doi.org/10.1245/s10434-015-4803-x)

    • Search Google Scholar
    • Export Citation
  • Mpaili E, Moris DM, Tsilimigras DI, Oikonomou D, Pawlik TM, Schizas D, Papalampros A, Felekouras E & Dimitroulis D 2018 Laparoscopic versus open adrenalectomy for localized/locally advanced primary adrenocortical carcinoma (ENSAT I-III) in adults: is margin-free resection the key surgical factor that dictates outcome? A review of the literature. Journal of Laparoendoscopic and Advanced Surgical Techniques 28 408414. (https://doi.org/10.1089/lap.2017.0546)

    • Search Google Scholar
    • Export Citation
  • Mwandila M, Waller H, Stott V & Mercer P 2010 A case of a testosterone-secreting oncocytic adrenocortical carcinoma. New Zealand Medical Journal 123 8082.

    • Search Google Scholar
    • Export Citation
  • Ohtake H, Kawamura H, Matsuzaki M, Yokoyama E, Kitajima M, Onizuka S & Yamakawa M 2010 Oncocytic adrenocortical carcinoma. Annals of Diagnostic Pathology 14 204208. (https://doi.org/10.1016/j.anndiagpath.2009.06.006)

    • Search Google Scholar
    • Export Citation
  • Panizzo V, Rubino B, Piozzi GN, Ubiali P, Morandi A, Nencioni M & Micheletto G 2018 Laparoscopic trans-abdominal right adrenalectomy for a large primitive adrenal oncocytic carcinoma: a case report and review of literature. American Journal of Case Reports 19 10961102. (https://doi.org/10.12659/AJCR.910259)

    • Search Google Scholar
    • Export Citation
  • Pennanen M, Heiskanen I, Sane T, Remes S, Mustonen H, Haglund C & Arola J 2015 Helsinki score: a novel model for prediction of metastases in adrenocortical carcinomas. Human Pathology 46 404410. (https://doi.org/10.1016/j.humpath.2014.11.015)

    • Search Google Scholar
    • Export Citation
  • Peynirci H, Dik N & Ersoy C 2018 Oncocytic neoplasms; rare adrenocortical tumours: a report of eleven patients. Endokrynologia Polska 69 682687. (https://doi.org/10.5603/EP)

    • Search Google Scholar
    • Export Citation
  • Raymond VM, Everett JN, Furtado LV, Gustafson SL, Jungbluth CR, Gruber SB, Hammer GD, Stoffel EM, Greenson JK & Giordano TJ et al. 2013 Adrenocortical carcinoma is a lynch syndrome-associated cancer. Journal of Clinical Oncology 31 30123018. (https://doi.org/10.1200/JCO.2012.48.0988)

    • Search Google Scholar
    • Export Citation
  • Renaudin K, Smati S, Wargny M, Al Ghuzlan A, Aubert S, Leteurtre E, Patey M, Sibony M, Sturm N & Tissier F et al. 2018 Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation. Modern Pathology 31 17081716. (https://doi.org/10.1038/s41379-018-0077-8)

    • Search Google Scholar
    • Export Citation
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