The Role of Biomarkers in Adrenocortical Carcinoma

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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9020174

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy arising from the adrenal cortex often with unexpected biological behavior. It can occur at any age, with two peaks of incidence: in the first and between fifth and seventh decades of life. Although ACC are mostly hormonally active, precursors and metabolites, rather than end products of steroidogenesis are produced by dedifferentiated and immature malignant cells.

adrenocortical carcinoma biomarkers steroidogenesis pathophysiology hormones

1. Pathogenesis of Adrenocortical Cancer

The adrenal cortex is divided into three zones: zona glomerulosa, zona fasciculata and zona reticularis where three main pathways of steroidogenesis occur. Adrenocortical carcinoma is a rare malignancy originating from the cortex of the adrenal gland with a poor prognosis due to its aggressive nature and unresponsiveness to conventional chemotherapeutic strategies. Although most ACC cases are sporadic and without a known cause, a minority of cases occur within other syndromes. The most common of these are Li-Fraumeni syndrome (TP53 gene germline and somatic mutation), Lynch syndrome (MSH2, MLH1, MSH6, PMS2, EPCAM genes), multiple endocrine neoplasia type 1 (MEN1 gene), Beckwith–Wiedemann syndrome (11p151 gene, IGF-2 overexpression), familial adenomatous polyposis (FAP gene, β catenin somatic mutations), neurofibromatosis type 1 (NF1 gene) and Carney complex (PRKAR1A gene) ^[1]^[2]^[3]. In spite of evident progress, molecular mechanisms of ACC tumorigenesis have not been yet fully understood ^[4]. Several molecular alterations and signaling pathways are thought to have a main role in tumor development. Monoclonality indicates that tumor progression is the end result of an intrinsic genetic tumor driver mutation ^[5]. Most common mutations implicated in sporadic ACC are insulin-like growth factor 2 (IGF2), β-catenin (CTNNB1 or ZNRF3) and TP53 mutations ^[6]^[7]^[8].

The main proposed oncogene in ACC tumorigenesis is insulin-like growth factor 2. The IGF-2 gene is located at 11p15 region that consists of a telomeric domain including the IGF-2 and H19 that might modulate IGF-2 expression and a centromeric domain including cyclin dependent kinase inhibitor (CDKNIC) involved in the G1/S phase of the cell cycle ^[5]. IGF-2 gene encodes IGF-2 protein and it is expressed by both fetal and adult adrenal glands and as a part of complex signaling system which plays an important role in normal growth and development, cell survival and proliferation as well as in malignant alteration ^[9]. IGF-2 overexpression was proven in more than 85% of ACCs although it is low or absent at the beginning of clonal proliferation ^[10]. Different studies have shown that IGF2 mRNA expression was 10–20-fold higher and IGF2 protein expression 8–80-fold greater in ACC compared to normal adrenal glands or adrenocortical adenomas (ACA), speculating that different IGF2 concentrations could be responsible for different biological behaviors of ACC ^[11]^[12]^[13]^[14]^[15]^[16]. IGF2 activates tyrosine kinase receptors that in turn lead to mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation. Activated Akt is then able to trigger the subsequent activation of the mammalian target of rapamycin (mTOR) pathway ^[16]. These pathways are involved in proliferation, survival, and metastasis of cancer cells ^[16].

Another signaling pathway included in ACC tumorigenesis is the canonical Wnt/β-catenin pathway where β-catenin protein plays a central role. The Wnt signaling pathway is normally activated during embryonic development where β-catenin stimulates and maintains proliferation of adrenal cortical cells, but it is also required for cell renewal in the adult adrenal cortex ^[17]. It has a structural role in cell–cell adhesion, and it is a transcription cofactor with T-cell factor/lymphoid enhancer factor mediating transcriptional activation of target genes of the Wnt signaling pathway ^[17]. Constitutive activation of Wnt/β-catenin is involved in many tumor types and, in experimental studies, it has been shown to act as an adrenal oncogene ^[18]. The Wnt/beta-catenin pathway in ACC can be activated by CTNNB1 mutations and by ZNRF3 (zinc and ring finger protein 3) inactivation ^[18]. According to the data from the literature almost 50% of ACCs show increased cytoplasmic or nuclear β-catenin accumulation ^[19].

Tumor protein 53 (TP53, p53) is a protein product of tumor suppressor gene located on chromosome 17 (17p13.1). P53 plays a role in regulation of the cell cycle, apoptosis, genomic stability and activation of DNA repair proteins. It is the most frequently altered gene in sporadic cancers, with greater than 50% of human tumors harboring somatic mutation ^[5]^[20]. According to genomic analyses, germline mutations in TP53 were observed in 50–80% of children with sporadic ACC, while somatic TP53 mutation was observed in 20% to 30% of sporadic ACC patients where it correlates with poor outcome ^[21]. In immunohistochemical studies diffuse p53 staining correlates positively with increased Ki-67 expression ^[22].

2. Pathological Approach to Adrenocortical Carcinoma

Adrenocortical tumors are a unique group of tumors whose differentiation between adenomas and carcinomas is a great challenge even for pathologists since no single pathohistological marker indicates malignancy ^[23]. Pathological assessment, crucial for the diagnosis of ACC after surgical resection relies on morphological features, margin identification and immunohistochemical staining ^[24]. Biopsy of a specimen of adrenal tumors is usually contraindicated due to possible complications and the fact of it not being completely informative ^[25]. Relative indication remains to exclude/prove secondary etiology of non-functional adrenal tumor in patients with positive anamnesis of extra-adrenal neoplasm ^[25]. Weight and size of the resected tumor should be the first to raise the suspicion for malignancy ^[23]. In the literature, different cut off values can be found to determine it: >95, >50, >100 g, but also in some cases tumors <50 g had malignant potential ^[23]^[24]^[26]^[27]. Most morphological studies confirm the size of the malignant lesion to be greater than 50–65 mm, ranging from 20 to 196 mm ^[23]^[24]^[26]^[28]. It is important to keep in mind that tumor size might be underestimated by radiological investigation and not correlate with the real size of tumor lesion ^[28]^[29]. Except that above mentioned, further examination should include evaluation of capsule integrity and the presence of hemorrhage, necrosis and invasion ^[28].

Beside the classical form, adrenocortical carcinoma can have other rare histological variants like oncocytic, myxoid and sarcomatoid ^[30]. ACC arise from the different zones of the adrenal cortex and they most often have the cellular morphology characteristic of different adrenocortical cells ^[24]. According to the latest guidelines, immunohistochemical panel staining should be done, including steroidogenesis factor 1 (SF1), adrenocortical-specific marker or alternatively inhibin-alpha, calretinin and melan-A for identification of adrenocortical tumors, chromogranin A for identification of pheochromocytoma and paraganglioma as well as synaptophysin for both ^[25]. Adrenocortical cells express SF-1, a transcriptional factor, during fetal and adult life, mostly in the zona glomerulosa and fasciculate ^[31]. Experimental studies have confirmed that its high expression positively correlates with high mitotic count, high Ki-67 index, and high European Network for the Study of Adrenal Tumors (ENSAT) stage and negatively with loss of functionality, presence of oncocytic features and decreased survival ^[31]. Therefore, steroidogenic factor 1 can be used as diagnostic and prognostic marker in adrenocortical carcinoma ^[31]^[32].

Ki-67 is also routinely measured and, although nonspecific for ACC, it has a prognostic role. Ki-67 is a protein expressed in all cell cycle phases except G0 and represents a cell proliferation index. Ki-67 labeling index of more than 5% confirms the diagnosis of ACC ^[2]^[28]. Ki67 index >10% correlates with higher risk of recurrence in ACCs and it is associated with worse overall survival in patients with advanced disease or rapid disease recurrence ^[28]^[33]. Although practical utility of Ki-67 staining was indisputable and confirmed in many studies, one should keep in mind that it is hard to set a diagnostic threshold because of possible interobserver variations ^[34]. According to some authors, a combination of insulin-like growth factor 2 (IGF2) and Ki67 index might be useful for differentiating malignant etiology of adrenal masses ^[35]^[36]. Beside abovementioned markers, steroidogenic enzymes, p53, cyclin E and β-catenin expression might be also histologically analyzed ^[2]. Several novel markers and some other roles of already known biomarkers were investigated in experimental studies using immunohistochemistry (± other methods) on a different number of patients with benign and malign adrenal tumors. The aim of analyses was to elucidate their utility in the diagnostic approach of discriminating malignant lesions, to investigate possible pathophysiological role and, finally, to analyze their prognostic and targeted therapy efficiency (Table 1). Further studies on larger cohorts are needed for their implementation in routine praxis.

Table 1. Review of novel immunohistochemically analyzed markers of adrenocortical carcinoma.

Marker	Definition/Role	Clinical Significance/Result	Number of Patients with Adrenocortical Carcinoma	Ref.
Metallothionein protein (MT) Minichromosome maintenance protein-2 (MCM2)	MT: scavengers of intracellular reactive oxygen species; overexpressed in various human tumors; MCM2: involved in the initiation of eukaryotic genome replication	-MT: no correlation with stage IV carcinoma -MCM2: positive correlation with Weiss revisited score, mitotic rate on histology, stage IV carcinoma	14	^[37]
Minichromosome maintenance protein complex MCM-3, 5, 7	Replication-licensing proteins; increased levels of MCM are observed in dysplastic and neoplastic cells	-higher levels in ACC of MCM-3, MCM-7, but not MCM-5; -proliferative and diagnostic markers in discerning benign and malignant adrenocortical tumors.	3	^[38]
Programmed death ligand (PD-L1 and 2)	Regulation of immune response; highly expressed in several cancers	-all tumor specimens were negative for PD-L1 expression; -PD-L2 is expressed commonly in adrenocortical adenomas samples	14; 34	^[39]^[40]
Sterol-O-acyl transferase 1 (SOAT1)	Involved in cholesterol esterification and lipid droplet formation; SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC	-37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2) -Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC -SOAT1 expression was not correlated with recurrence-free survival, progression-free survival and disease-specific survival in ACC patients with mitotane monotherapy	112; 231	^[41]^[42]
Somatostatin receptors (SSTRs)	Expressed in both normal tissues and solid tumors; part of distinct signaling cascades	-ACC can express SSTRs; SSTRs-based peptide receptor radionuclide therapy may represent a potential treatment opportunity for a minority of patients with advanced ACC	19	^[43]
Chemokine receptor (CXCR 4 and 7)	Chemokine receptors have a negative impact on tumor progression in several human cancers	-High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue; strong membrane expression of CXCR4 and CXCR7 in 50% of ACC; -strong cytoplasmic CXCR4 staining was more frequent in metastases compared to primaries and local recurrences; -CXCR4 staining positively and CXCR7 negatively correlated with Ki67.	187	^[44]
LH/CGR	Luteinizing hormone and/or chorionic gonadotropin (LH/CG) exert direct actions on the adrenal cortex and are involved in the adrenal pathology	-positive in the whole cytoplasm, but weak or absent in cell membranes; the loss of membrane localization of LH/CGR in adrenocortical cancer suggests the alteration of receptors’ function.	5	^[45]
Fascin-1 (FSCN1) and FOXM1	Epithelial–mesenchymal transition (EMT) related genes	-FSCN1 and FOXM1 over-expression in ACC; -novel independent prognostic markers in ACC; -potential therapeutic target to block tumor spread	37; 51	^[46]^[47]
Topoisomerase II alpha (TOP2A); thymidylate synthase (TS)	Prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines	-TOP2A expression was associated with better after EDP-M (etoposide, doxorubicin and cisplatin plus mitotane) -TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients	39	^[48]
Insulin like growth factor 2 (IGF2) IGF1 receptor (IGF1R)	Main pathway in ACC tumorigenesis	-in addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered -IGF1 overexpression was associated with SLC12A7 overexpression and non-functional, early-stage and larger tumors	17; 33	^[49]^[50]
CD276-(B7-H3)	Inhibitory role in adaptive immunity; in malignant tissues, B7-H3 is an immune checkpoint molecule	-positive expression on the cell membrane and in the cytoplasm of cancer cells or tumor-associated vascular cells -vascular expression of CD276 associated with local aggression	48	^[51]
c-myc	Proto-oncogene	-strong cytoplasmic c-myc expression and weak nuclear expression in ACC associated with malignancy and shorter survival	31	^[52]
Phosphorylated mTOR	Part of signaling pathway	-p-mTOR expression in 32% cases, with a moderate or strong cytoplasmic reactivity -p-mTOR was also negative in tumors with high Weiss Score,	58	^[53]
Pituitary-tumor transforming gene (PTTG1)	Modulate cancer invasiveness and response to therapy	-increased nuclear protein expression of PTTG1 in ACC -PTTG1 correlated with Ki-67	20; 14	^[54]
Glypicin-3 (GPC-3)	Role in the control of cell division and growth regulation; role in distinguishing hepatic lesions	-GPC-3 positivity rare in ACC, but possible, especially of extra-adrenal ACC	1; 2	^[55]^[56]
E-/P-/N-cadherins, MMP-2/-9 and caveolin-1 ZEB-1/-2, Slug Oct3/4, LIN28, SOX2, SO17, NANOG, CD133, nestin	Epithelial–mesenchymal transition (EMT)-associated markers (E-/P-/N-cadherins, MMP-2/-9 and caveolin-1) Downstream transcriptional regulators of EMT-related signaling pathways (ZEB-1/-2, Slug) Stem cell factors (Oct3/4, LIN28, SOX2, SO17, NANOG, CD133, nestin) Markers of adrenocortical origin/tumorigenesis (SF-1, β-catenin, p53)	ACC with sarcomatous areas: -SF-1 and E-/P-/N-cadherins positive only in the epithelial component of all cases, whereas the nonepithelial components were mainly enriched for nestin, ZEB-1, and MMP-2/-9 -β-Catenin demonstrated an aberrant nuclear localization in the sarcomatoid component whereas p53 was strongly positive in the nonepithelial constituent	6	^[57]
Livin/BIRC7	Member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases	-over-expressed in ACC, localized in both cytoplasm and nuclei.-the ratio between cytoplasmic and nuclear staining was significantly higher in ACC than in ACA	192	^[58]
Retinoic acid receptor responder 2 (RARRES2)	An immune-dependent tumor suppressor	-compared to normal adrenocortical tissues, expression was significantly lower in benign tumors, and even lower in ACC samples.	19	^[59]
Adiponectin receptors	Adiponectin: involved in regulating glucose levels as well as fatty acid breakdown	-the expression of Adipo R1 and R2 receptors was associated with ACC diagnosis	20	^[60]
Stathmin1 (STMN1)	Cytosolic protein involved in microtubule dynamics; implicated in carcinogenesis and aggressive behavior in multiple malignancies	-significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues	13	^[61]
MCT1, MCT2, MCT4, CD147, CD44, GLUT1 CAIX	MCT1 and MCT4 mediate monocarboxylate efflux from cells, while MCT2 is involved in monocarboxylate uptake; these transporters require co-expression with chaperones for proper plasma membrane localization and activity; the main chaperone is CD147; CD44 has also been recently described as a MCT chaperone	-increased membranous expression of MCT4, GLUT1 and CAIX in ACC -MCT1, GLUT1 and CAIX expressions associated with poor prognostic variables -MCT2 membranous expression was associated with favorable prognostic parameters. -cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival -cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival.	78	^[62]
VAV2	VAV2 -guanine nucleotide exchange factor; oncogene	-VAV2 expression correlated with Ki-67 index and progression free survival and overall survival	171	^[63]
Cytochrome P450 genes	P450 overexpression potentiates adrenocortical carcinoma chemoresistance.	-analysis confirmed protein overexpression	29	^[64]
Steroidogenic acute regulatory protein (StAR), CYP11B1, CYP11B2, YP17A1	Key proteins involved in the steroidogenesis cascade	-CYP11B1, StAR and CYP17A1 expression was lower in ACC; ACC presented co-staining cells for CYP11B1 and CYP11B2; CYP11B1 had the most discriminative power to distinguish ACC from ACA with a sensitivity of 100%, specificity of 92%	14	^[65]
Progesterone receptor	Protein activated by the steroid hormone progesterone	-in 50% samples, IHC (immunohistochemistry) revealed a weak expression of progesterone receptor	8	^[66]
D2-40; CD-31	D2-40 antibody for lymph vessels CD-31 antibody for blood vessels	-D2-40 expression lower in ACC and correlated positively with the expression of StAR; -CD31 expression higher in ACC	15	^[67]
Inhibin, D2-40, synaptophysin	Inhibin downregulates FSH (follicle-stimulating hormone) synthesis and secretion; D2-40 may be a useful marker for distinguishing primary adrenal cortical neoplasms from both metastatic renal cell carcinoma and pheochromocytoma; Synaptophysin: major synaptic vesicle protein	-patients with any negative staining had shorter cancer-specific survival than ones with positive staining -negative staining for inhibin, D2-40 and synaptophysin and Ki-67 expression ≥7% were associated with poorer prognosis	30	^[68]
Excision repair cross complementing group 1 (ERCC1)	Role in the repair of platinum-induced DNA damage	-high ERCC1 expression was observed in 66% of ACC samples	146	^[69]
Sphingosine kinase 1 (SphK1)	Oncogene	-over-expression of SphK1 protein in the carcinomas compared with adenomas	24	^[70]
N-cadherin	Aberrant expression of N-cadherin plays important role in ACC tumorigenesis	-N-cadherin downregulation was observed in 100 % of ACC	24; 15	^[19]^[71]
Telomerase reverse transcriptase (TERT)	Catalytic subunit of the telomerase complex	-telomerase nuclear expression was present in 26.6% of ACC and in 45.5% of non-functioning adenomas	15	^[71]
Isocitrate dehydrogenase (IDH) R132H mutation	Metabolic enzyme, ubiquitous in all cells; mutations of IDH play a prognostic or predictive role in several neoplasms	-positive IDH1 R132H staining correlated with a better prognosis among patients with ACC; it did not distinguish between local and metastasized tumors.	33	^[72]
Indoleamine 2,3-dioxygenase 1 (IDO-1)	An immune checkpoint molecule	-IDO-1 is expressed in a majority of ACC samples; its expression in tumor tissue is associated with PD-L2 expression, and expression in stroma is associated with CD8+ cell infiltration.	32	^[73]

ACCs can be graded into low- and high-grade based on their mitotic rates (≤20 mitoses per 50 high-power fields (HPF) or >20 mitoses per 50 HPF ^[74]. In clinical practice, several scoring systems have been developed to help distinguish malignant from benign adrenal tumors. The most widely used diagnostic tool is the Weiss score. The Weiss score includes nine histopathological parameters, related to tumor and cellular structure as well as invasion. A score of ≥3 suggests malignancy ^[28]. For an oncocytic variant of ACC Lin–Weiss–Bisceglia (LWB) scoring is proposed and Wieneke criteria are more reliable than Weiss scoring for the pediatric population ^[75]^[76]^[77].

Another simplified diagnostic algorithm termed the Reticulin algorithm was proposed several years ago, with a sensitivity and specificity of 100% for ACC ^[35]. It includes evaluation of disruption of the reticular network (highlighted by histochemical staining) and at least one of following parameters: mitotic rate >5/50 high-power fields, necrosis and vascular invasion ^[35]. In 2015, the Helsinki score was developed for more precisely predicting occurrence of metastases in adrenocortical carcinoma ^[78]. According to Duregon et al., who performed analysis on 225 ACC patients, it presents the most useful tool with an impact on prognosis, outperforming other prognostic parameters such as clinical stage, mitotic index and Ki-67 proliferation index, also applicable in all histological variants of disease ^[30]. The Helsinki score accounts for morphological (mitoses and necrosis) and immunohistochemistry parameters (the absolute value of the Ki-67 proliferation index), meaning 3× mitotic rate greater than 5/50 high-power fields + 5× presence of necrosis + proliferation index in the most proliferative area of the tumor ^[30]. With a cut off value of 8.5, this scoring has 100% sensitivity and 99.4% specificity for diagnosing metastatic ACC ^[35]^[78]. In summary, the Helsinki and Weiss score are predictors of poor prognosis, while the Helsinki score and Ki-67 index are the best predictors of disease-related death ^[30]. It is important to mention that in different studies, some other cut off values of the abovementioned scores were proven, i.e., <13 and ≥19 for the Helsinki score ^[30]. Further studies are needed to elucidate this area and its reproducibility.

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Maja Mizdrak

Tina Tičinović Kurir

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1. Pathogenesis of Adrenocortical Cancer

2. Pathological Approach to Adrenocortical Carcinoma

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