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.
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 | [85][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 | [86][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 | [87,88][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 | [89,90][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 | [91][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 | [92][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 | [93][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 | [94,95][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 | [96][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 | [97,98][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 | [99][51] |
c-myc | Proto-oncogene | -strong cytoplasmic c-myc expression and weak nuclear expression in ACC associated with malignancy and shorter survival | 31 | [100][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 | [101][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 | [102][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 | [103,104][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 | [105][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 | [106][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 | [107][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 | [108][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 | [109][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 | [110][62] |
VAV2 | VAV2 -guanine nucleotide exchange factor; oncogene | -VAV2 expression correlated with Ki-67 index and progression free survival and overall survival | 171 | [111][63] |
Cytochrome P450 genes | P450 overexpression potentiates adrenocortical carcinoma chemoresistance. | -analysis confirmed protein overexpression | 29 | [112][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 | [49][65] |
Progesterone receptor | Protein activated by the steroid hormone progesterone | -in 50% samples, IHC (immunohistochemistry) revealed a weak expression of progesterone receptor | 8 | [113][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 | [114][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 | [115][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 | [116][69] |
Sphingosine kinase 1 (SphK1) | Oncogene | -over-expression of SphK1 protein in the carcinomas compared with adenomas | 24 | [117][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 | [25,118][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 | [118][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 | [119][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 | [120][73] |