Shift from Conn’s syndrome to Cushing’s syndrome in a recurrent adrenocortical carcinoma

in European Journal of Endocrinology
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  • 1 Department of Histology, Microbiology and Medical Biotechnologies, University of Padova,Via A. Gabelli 63, I-35121 Padova, Italy 1Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy and 2Departments of Pathology and 3Medical and Surgical Sciences, University of Padova,Via A. Gabelli 63, I-35121 Padova, Italy

Objective: Adrenocortical tumors may originate from the zona glomerulosa, zona fasciculata, or zona reticularis and be associated with syndromes due to overproduction of mineralocorticoids, glucocorticoids, or androgens respectively. We report an unusual case of recurrent adrenocortical carcinoma (ACC), which seems to contradict the paradigm of functional adrenal zonation.

Case report: A male patient presented with severe primary aldosteronism due to an ACC, which relapsed after adrenalectomy and adjuvant mitotane therapy. After removal of the tumor recurrence and eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin, the patient presented again with ACC masses, but in association with overt Cushing’s syndrome and normal aldosterone levels.

Methods and results: Extensive pathologic examination showed that this shift in steroid hormone production was paralleled by an attenuation of tumor cell atypia and polymorphism, whereas gene expression profile analysis demonstrated a change in expression of adrenal steroidogenic enzymes. Moreover, cancer progression was associated with overexpression of the inhibin-α subunit, which could have contributed to the phenotypic changes.

Conclusions: This case of recurrent ACC demonstrates that adrenocortical cells can reverse their differentiation program during neoplastic progression and change their specific hormone synthesis, as a consequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a consequence of chromosome amplification induced by chemotherapy. These findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis in order to dissect thoroughly the biology of cancer.

Abstract

Objective: Adrenocortical tumors may originate from the zona glomerulosa, zona fasciculata, or zona reticularis and be associated with syndromes due to overproduction of mineralocorticoids, glucocorticoids, or androgens respectively. We report an unusual case of recurrent adrenocortical carcinoma (ACC), which seems to contradict the paradigm of functional adrenal zonation.

Case report: A male patient presented with severe primary aldosteronism due to an ACC, which relapsed after adrenalectomy and adjuvant mitotane therapy. After removal of the tumor recurrence and eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin, the patient presented again with ACC masses, but in association with overt Cushing’s syndrome and normal aldosterone levels.

Methods and results: Extensive pathologic examination showed that this shift in steroid hormone production was paralleled by an attenuation of tumor cell atypia and polymorphism, whereas gene expression profile analysis demonstrated a change in expression of adrenal steroidogenic enzymes. Moreover, cancer progression was associated with overexpression of the inhibin-α subunit, which could have contributed to the phenotypic changes.

Conclusions: This case of recurrent ACC demonstrates that adrenocortical cells can reverse their differentiation program during neoplastic progression and change their specific hormone synthesis, as a consequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a consequence of chromosome amplification induced by chemotherapy. These findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis in order to dissect thoroughly the biology of cancer.

Case report

A 42-year-old man presented with severe hypertension (blood pressure, 200/120 mmHg) and hypokalemia (serum K+, 2.2 mmol/l). Endocrine evaluation showed elevated plasma and urinary aldosterone levels (upright plasma aldosterone, 1371 pmol/l; normal values, 140–830 pmol/l) with suppressed plasma renin activity (PRA) (upright PRA, 0.1 ng/ml per h; normal values, 1.5–6 ng/ml per h), whereas cortisol, adrenal androgens and testosterone were within the normal range (Fig. 1). In particular, 24 h urinary free cortisol was 135 nmol/24 h (normal values, 82–330 nmol/l); plasma cortisol at 0800 h was 415 nmol/l (normal values, 138–550 nmol/l); at 1800 h, plasma cortisol was 287 nmol/l; and in the morning, 1 mg dexamethsone suppression test was 115 nmol/l (normal response, <138 nmol/l). Abdominal computed tomography (CT) scan demonstrated a 5 cm right adrenal mass, which was diagnosed as adrenocortical carcinoma (ACC) at histologic examination. After adrenalectomy, the patient received adjuvant mitotane therapy at doses up to 10 g/day, but after 9 months the patient presented again with isolated severe aldosteronism associated with a 3 × 5 cm tumor relapse in the right adrenal region and lymph-node and skin metastasis. The patient underwent complete removal of the tumor masses, followed by eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin for residual disease. Notwithstanding initial control of the disease, tumor recurrence was identified by CT scan after about 8 months. Clinical examination demonstrated weight gain with central obesity (body-mass index change from 26 kg/m2 at diagnosis to 31 kg/m2), whereas endocrine investigations revealed elevated 24 h urinary free cortisol (528 nmol/24 h), plasma cortisol (plasma cortisol at 0800 h, 615 nmol/l), plasma dehydroepiandrosterone sulfate (DHEA-S) (32.7 μmol/l; normal values, 0.5–9.0 μmol/l), and androstenedione (26.4 nmol/l; normal values, 2.0–9.2 nmol/l) values; undetectable plasma adrenocorticotropic hormone (ACTH); and normal levels of plasma aldosterone and PRA. Plasma and urinary cortisol were unresponsive to the high-dose dexamethasone suppression test. The patient was operated again to remove three abdominal masses of 7, 5.5 and 5 cm in maximum diameter, and subsequently treated with second-line chemotherapy with irinotecan and gemcitabine. Eventually, the patient died from persistent hypercortisolism and metastatic disease at 24 months after diagnosis (Fig. 1).

Results and discussion

ACC is a rare and very aggressive cancer with poor prognosis. About half of cases are hormonally active and associated with clinical features of hypercortisolism (Cushing’s syndrome), virilization, feminilization, or, rarely, primary aldosteronism (Conn’s syndrome). Mixed syndromes due to overproduction of different steroid hormones and steroid precursors are also frequently observed.

This case of recurrent ACC attracted our attention because of the atypical clinical presentation, characterized by a shift from primary aldosteronism to Cushing’s syndrome during tumor progression. This shift in adrenal steroid synthesis, which has been very rarely reported in the literature (13), seems to contradict the paradigm of functional adrenal zonation, according to which the three zones of the adult adrenal, that is, zona glomerulosa, zona fasciculata and zona reticularis, have specialized steroido-genetic activity, being committed to produce mineralocorticoids, glucocorticoids and androgens respectively.

In order to investigate the mechanism at the basis of this endocrine shift, we performed a thorough pathologic, genetic and gene expression profile analysis of the primary lesion and its recurrences. The patient gave written, informed consent for the scientific evaluation of the tumor samples.

Pathologic examination revealed quite variable findings, since cells of the primary tumor and the first recurrence showed great polymorphism and atypia, frequent and atypical mitoses, and no evident organoid growth pattern (Fig. 2A). In contrast, metastases of the second relapse showed monomorphism of the tumor cell population with a nodular growth pattern simulating an organoid structure. The neoplastic cells had large eosinophilic cytoplasm, but this was more regular than in the primary ACC and first recurrence, and nuclei were less variable in size and chromatin distribution (Fig. 2B).

Sequence analysis of candidate genes (i.e., TP53, PTEN, GNAS1, GNAI2, CDKN1C, MEN1, PRKAR1A, INHA and APC) typically involved in adrenal tumorigenesis failed to demonstrate pathologic mutations either in the primary tumor or in recurrences, whereas measurement of mRNA levels of ACC marker genes (i.e., IGF2, H19, CDKN1C, EGFR and TOP2A) by quantitative real-time RT–PCR demonstrated very high IGF2 and TOP2A mRNA levels and underexpression of H19 and CDKN1C in both primary primary tumor and metastases, as typically observed in ACC (4).

DNA microarray analysis and quantitative real-time RT–PCR demonstrated that the expression pattern of steroidogenic enzymes was concordant with endocrine activity of the ACC masses. In fact, mRNA levels of CYP11B2 (aldosterone synthase) were extremely high in the aldosterone-producing tumors but very low in the second relapse, which, in contrast, had high mRNA levels of genes encoding enzymes involved in the production of cortisol and adrenal androgens, such as CYP17, CYP21 and SULT2A1 (Table 1 and Fig. 2D–F) (5). Of interest, microarray analysis (performed with microarray glass slides containing 70 mer oligonucleotide sequences of 21 329 human genes, produced by CRIBI Core Facility, University of Padova, Italy) also showed that the most overexpressed genes in the second cortisol-secreting ACC recurrence, as compared with the aldosterone-producing primary ACC and first relapse, included a large number of genes mapping to the 19q13.3–4 chromosomal region. Among these genes, there were a large cluster of cytochrome P450 genes involved in the metabolism of steroids and xenobiotics (6) (e.g., CYP2B6, CYP2S1 CYP2A7) and the INHA gene, encoding the inhibin α-subunit (Table 2). Overexpression of cytochrome P450 genes leading to increased inactivation of anti-cancer drugs has been linked to chemotherapy resistance (7). Chromosomal gains and amplifications in 19q13 are often found in ACC (8), and, in our case, they could indeed have occurred during chemotherapy, causing gene overexpression. The product of the SULT2A1 gene, DHEA sulfotranspherase, also located in 19q13.3–4, normally sulfates DHEA to DHEA-S, as well as pregnenolone and 17α-hydroxypregenolone to their sulfated metabolites, removing these substrates from mineralocorticoid and glucocorticoid pathways respectively (9). SULT2A1 overexpression, in the presence of high levels of CYP17 and CYP21, might have shifted aldosterone biosynthesis to both cortisol and androgen biosynthesis. These findings are in accordance with the clinical shift from Conn’s syndrome to Cushing’s syndrome seen in our patient.

Overexpression of the inhibin α-subunit in the cortisol-producing ACC recurrence (Fig. 2C) could have also contributed to the shift from mineralocorticoid to glucorticoid formation. The inhibin α-subunit is highly expressed in the fetal zone of the developing adrenal cortex and in the zona reticularis of adult adrenal cortex and tumors derived thereof. In this regard, the inhibin α-subunit has been found to stimulate cortisol and androgen secretion by antagonizing activin signaling through a dominant-negative effect (10).

In conclusion, this case of recurrent ACC, characterized by the sequential presentation of two endocrine syndromes, Conn’s and Cushing’s syndromes, demonstrates that adrenocortical cells can reverse their differentiation program during neoplastic progression and change their specialized hormone production, as a consequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a consequence of chromosome amplification induced by chemotherapy, even though we cannot exclude other molecular mechanisms, such as point mutations in steroidogenic enzymes or transcription factors, chromosomal translocations, and clonal progression of cells with different functional properties. Shift in endocrine activity has been also recently observed in a case of small-cell lung cancer treated by chemotherapy (11). Our findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis to dissect thoroughly the biology of cancer.

Acknowledgements

This study was supported by grant no. RSF 168/04 from the Veneto Region and by funds from IOV (Istituto Oncologico Veneto) to G. Palù.

Table 1

Results of microarray analysis of expression of steroidogenic enzymes and transcription factors in the recurrent ACC vs normal adrenocortical tissues.

DescriptionGeneNormal adrenalaRatio ACC1/normalbRatio ACC2/normalbRatio ACC2/ACC1b
aSignal intensity values in normal adrenocortical tissues; bratios >2 (i.e., overexpressed genes) are in boldface, ratios <0.5 (i.e., underexpressed genes) are in boldface and italic; ACC1: primary ACC; ACC2; second ACC recurrence.
Cytochrome P450, subfamily I, polypeptide 2CYP1A28.591.921.991.49
P450 (cytochrome) oxidoreductasePOR5.902.162.391.11
Cytochrome P450, subfamily XVIICYP175.440.424.866.67
Steroidogenic acute regulatory proteinSTAR5.402.162.531.50
24-dehydrocholesterol reductaseDHCR245.020.941.351.91
Nuclear receptor subfamily 4, A1NR4A14.981.952.281.16
Cytochrome P450, subfamily XXIA, polypeptideCYP21A24.662.402.701.31
Cytochrome P450, subfamily IIB, polypeptide 6CYP2B63.911.272.313.14
Cytochrome P450, subfamily IIS, polypeptide 1CYP2S13.531.422.793.93
Hydroxysteroid (17-beta) dehydrogenase 1HSD17B13.302.932.491.66
Cytochrome P450, subfamily XIB, polypeptide 1CYP11B12.502.131.110.81
Cytochrome P450, subfamily IIA, polypeptide 7CYP2A72.451.673.092.98
Hydroxyacyl-coenzyme A dehydrogenase, type IIHADH22.201.561.931.78
Hydroxysteroid (3-beta) dehydrogenase 2HSD3B22.172.222.091.29
Cytochrome P450, subfamily XIA (cholesterol sec)CYP11A2.171.281.601.76
Hydroxysteroid dehydrogenase, 3 beta 1HSD3B12.124.515.712.53
7-Dehydrocholesterol reductaseDHCR72.121.983.733.14
Steroid sulfotransferase 2A1, DHEA-preferringSULT2A12.010.422.434.47
Hydroxysteroid (17-beta) dehydrogenase 7HSD17B71.971.163.082.40
Aldo-keto reductase, 7A2AKR7A21.951.421.291.28
Steroid sulfotransferase 1C2SULT1C21.742.582.681.22
Steroid sulfatase (microsomal), isozyme SSTS1.600.740.890.88
Ferrodoxin reductaseFDXR1.583.192.851.21
Cytochrome P450, subfamily IIC9CYP2C91.561.400.860.69
Steroidogenic factor-1 (SF-1)NR5A11.511.381.531.15
Nuclear receptor subfamily 4, A2NR4A21.480.370.220.61
Cytochrome P450, subfamily XIB, polypeptide 2CYP11B21.435.101.190.40
Aldo-keto reductase, 1B1AKR1B11.361.261.092.47
Cytochrome b5CYB51.170.490.792.67
Hydroxysteroid (17-beta) dehydrogenase 4HSD17B41.121.261.231.26
Aldo-keto reductase, 1A1AKR1A11.090.890.590.65
Steroid sulfotransferase 1C1SULT1C10.980.861.210.71
Steroid reductase, alpha polypeptide 1SRD5A10.980.840.810.45
Aldo-keto reductase, 1B10AKR1B100.960.220.390.17
Aldo-keto reductase, 1D1AKR1D10.890.620.350.25
Steroid sulfotransferase, 2B1SULT2B10.880.800.540.34
Liver receptor homolog 1 (LRH-1)NR5A20.830.900.600.24
Cytochrome P450, subfamily XIXCYP190.810.190.391.31
Aldo-keto reductase, 1C1AKR1C10.691.010.360.84
Hydroxysteroid (17-beta) dehydrogenase 2HSD17B20.600.720.480.19
Steroid sulfotransferase, 1B1SULT1B10.590.550.661.21
Hydroxysteroid (11-beta) dehydrogenase 2HSD11B20.550.310.731.88
Steroid sulfotransferase, 1A2SULT1A20.551.661.032.03
Steroid sulfotransferase, 1A3SULT1A30.491.371.171.54
Hydroxysteroid (11-beta) dehydrogenase 1HSD11B10.430.801.701.29
Hydroxysteroid (17-beta) dehydrogenase 3HSD17B30.420.621.792.12
Steroid sulfotransferase, 1A1SULT1A10.310.680.901.26
Table 2

Transcripts expressed at >3 threefold higher or lower in the second ACC recurrence vs the primary ACC.

DescriptionFunctionMapUniGeneGeneRatio
Overexpressed genes
Ubiquitin carboxyl-terminal esterase L1Ubiquitin hydrolysis; neuroendocrine tissues4p1476 118UCHL111.40
Synuclein, gammaOncogene10q23349470SNCG10.06
ClusterinDownregulated in prostate cancer8p2175 106CLU7.79
Chymotrypsinogen B1Serine protease16q2374 502CTRB17.05
Cytochrome P450, subfamily XVIISteroid 17-alpha-hydroxylase10q24.31363CYP176.67
Paternally expressed 3Growth-promoting functions, but also tumor suppressor19q13.4139033PEG36.25
K562 cell-derived leucine-zipper-like protein 1Transcription factor19q13.4331 854LOC571065.91
AdlicanVEGF receptorXp22.3372 157DKFZp564119225.78
Zinc finger protein 573Regulation of transcription19q13.13278871ZNF5735.59
K1AA1198 proteinZink-finger protein 49019p13.2175475KIAA11985.38
SynaptophysinAdrenocortical neoplasm marker, cholesterol bindingXp11.2375 667SYP5.19
Leukocyte receptor cluster member 5tRNA splicing19q13.415 580LENG54.82
Retinol binding protein 1, cellularRetinol transport, antitumor activity3q23101850RBP14.76
Solute carrier family 4, anion exchanger, member 3Anion transport2q361176SLC4A34.74
Protein phosphatase 1, regulatory subunit 14AInhibitor of smooth muscle myosin phosphatase19q13.1348037PPP1R14A4.73
HMT1 bnRNP methyltransferase-like 1Signal transduction21q22.3235887HRMT1L14.71
Solute carrier family 25Mitochondrial carrier with calcium-binding domains19q13.332 246SLC25A234.66
Sulfotransferase 2A, DHEA-preferring, member 1Steroid metabolism19q13.381 884SULT2A14.47
K1AA1415 proteinGuanine nucleotide exchange factor20q13.13109315KIAA14154.43
Inhibin, alphaActivin inhibitor activity2q33–361734INHA4.41
Filamin B, betaActin cytoskeleton organization3p14.381 008FLNB4.32
Cargo selection proteinSimilar to mannose-6-P receptor binding protein 119p13.3140452TIP474.26
Retinol dehydrogenase 13 (all-trans and 9-cis)Oxidoreductase activity19q13.42178617RDH134.19
Fatty acid desaturase 1Fatty acid biosynthesis11q12.2-q13.1132898FADS14.09
PRP31 pre-mRNA processing factor 31Retinitis pigmentosa, snRNP formation19q13.42183438PRPF314.08
Ubiquitin-conjugating enzyme E2CCell growth and malignant transformation20q13.1293 002UBE2C3.98
Stem-loop (histone) binding proteinHistone processing4p16.375 257SLBP3.95
Cytochrome P450, subfamily IIS, polypeptide 1Drug metabolism and cholesterol synthesis19q13.198 370CYP2S13.93
Neuronal pentraxin ICentral nervous system development17q25.1-q25.284 154NPTX13.92
Ectodermal-neural cortex (with BTB-like domain)Actin-binding protein5q12-q13.3104925ENC13.78
Niemann-pick disease, type C1Intracellular transport of cholesterol18q1176 918NCP13.72
Thioredoxin-like 4AElectron transport18q235074TXNL4A3.72
Actinin, alpha 4Actin-binding protein; tumorigenicity19q13182485ACTN43.70
Reticulon 4Neuroendocrine secretion2p16.365 450RTN43.70
Zinc-finger protein 83 (HPF1)Transcription factor19q13.3305953ZNF833.68
Protein tyrosine phosphatase, receptor type, HTumor suppressor19q13.4179770PTPRH3.65
Host cell factor C1 regulator 1 (XPO1 dependent)HCF-1 beta-propeller interacting protein16p13.3279581HCFC1R13.61
Anti-müllerian hormoneGonadal development19p13.3112432AMH3.60
Thioredoxin reductase 1Protection against oxidative stress18q2313 046TXNRD13.48
Pituitary tumor-transforming 1 interacting proteinFacilitates the nuclear translocation of PTTG121q22.3111126PTTG11P3.46
Thy-1 cell surface antigenTumor suppressor gene11q22.3-q23125359THY13.45
PorcupineProcessing of Wnt proteinsXp11.235326MG613.45
KRAB zinc-finger protein KR18Regulation of transcription19q13.41206882KR183.43
Tropomyosin 2 (beta)Structural constituent of muscle9p13.2-p13.1300772TPM23.40
Similar to zinc-finger protein 26819q13.42209430LOC916643.34
Thromboxane A2 receptorThromboxane A2 receptor activity19p13.389 887TBXA2R3.34
Serine carboxypeptidase 1Serine carboxypeptidase activity17q23.2106747SCPEP13.31
Growth hormone receptorGrowth factor5p13-p12125180GHR3.27
Liver-specific bHLH-Zip transcription factorReceptor activity19q13.1295 697LISCH73.26
Brain abundant, membrane attached signal protein 1Membrane bound protein5p15.1-p1479 516BASP13.26
CCR4-NOT transcription complex, subunit 3Transcription regulator activity19q13.4343571CNOT33.24
Dynein, cytoplasmic, light polypeptideInhibition of NOS activity12q24.235120PIN3.23
Plexin A1Semaphorin receptor activity3q21.3334666PLXNA13.23
Oxysterol binding protein-like 10Intracellular lipid receptor3p22.3285123OSBPL103.22
WD repeat domain 1819p13.3325321WDR183.22
Leukocyte receptor cluster member 8Receptor19q13.42348571LENG83.21
Clone MGC:9381 IMAGE:386558319q13.376 2773.19
Ovary-specific acidic protein4q31.1154140OSAP3.18
Stearoyl-CoA desaturaseFatty acid biosynthesis10q23-q24119597SCD3.16
Cytochrome P450, subfamily IIB, polypeptide 6Drug metabolism and cholesterol synthesis19q13.21360CYP2B63.14
7-dehydrocholesterol reductaseEndogenous cholesterol synthesis11q1311 806DHCR73.14
3-hydroxy-3-methylglutaryl-coenzyme A reductaseRate-limiting enzyme for cholesterol synthesis5q13.3-q1411 899HMGCR3.10
CNDP dipeptidase 2 (metallopeptidase M20 family)Metallopeptidase activity18q22.3273230CNDP23.09
Pro-oncosis receptor inducing membrane injury geneOncosis-like cell death11q22.1172089PORIMIN3.08
Aquaporin 2 (collecting duct)Water channel12q1237 025AQP23.07
Glutathione S-transferase A4Cellular defense against toxic compounds6p12.1169907GSTA43.07
Breast cancer anti-estogen resistance 1Signal transduction16q22-q23273219BCAR13.06
Nucleobindin 2Calcium-binding EF-hand protein11p15.1-p143164NUCB23.05
Cytochrome P450, subfamily IIA, polypeptide 7Drug metabolism and cholesterol synthesis19q13.2250615CYP2A73.05
Mitogen-activated protein kinase 4MAP kinase activity18q12-q21269222MAPK43.04
Underexpressed genes
Fatty acid binding protein 4, adipocyteFatty acid uptake, transport, and metabolism8q2183 213FABP40.05
Cell adhesion molecule with homology to LICAMNeural cell adhesion molecule3p26.1210863CHL10.08
Urotensin 2Vasoconstrictor1p36162200UTS20.10
37 kDA leucine-rich repeat protein7q22.1155545P37NB0.11
Plasticity related gene 3Lipid phosphate phosphatase activity9q31.1106825PRG-30.14
Hypothetical protein MGC109814p16.1115912MGC109810.15
Estrogen-related receptor gammaOrphan nuclear receptor1q41151017ESRRG0.16
Chemokine (C-X3-C motif) ligand 1Chemokine activity16q1380 420CX3CL10.19
Chromosome 20 open reading frame 10320p1222 920C20orf1030.20
Solute carrier family 25 member 15L-ornithine transporter activity13q1478 457SLC25A150.23
Growth differentiation factor 10Cell growth and differentiation10q11.222171GDF100.25
Fatty-acid-coenzyme a ligase, long-chain 5Long-chain-fatty-acid-CoA ligase activity10q2511 638FACL50.26
Putative nuclear proteinAcidic repeat containingXq13.1135167NAAR10.29
Cathepsin ZTumorigenesis20q13252549CTSZ0.29
Interferon, gamma-inducible protein 30Lysosomal thiol reductase19p13.114 623IFI300.30
Cytochrome P450, subfamily XIB, polypeptide 2Aldosterone synthesis8q21-q22184927CYP11B20.30
SecretinIntestinal hormone11p15.5302005SCT0.31
Maternally expressed 3Tumor suppressor14q32112844MEG30.32
NeurotriminCell adhesion, neuronal cell regonition11q25288433HNT0.32
Glutathione S-transferase M3 (brain)Detoxification of electrophilic compounds1p13.32006GSTM30.33
Figure 1
Figure 1

Plasma aldosterone and cortisol levels in a patient with ACC during the course of his disease. The red hatching indicates normal values; vertical hatching, upright plasma aldosterone, 140–830 pmol/l; horizontal hatching, plasma cortisol at 0800 h, 138–550 nmol/l. Mitotane doses are reported in grams per day; EDP: etoposide, doxorubicin, cisplatin; IG: irinotecan, gemcitabine.

Citation: European Journal of Endocrinology eur j endocrinol 153, 5; 10.1530/eje.1.02011

Figure 2
Figure 2

Pathologic examination of ACC specimens (A–C): A) hematoxylin and eosin (HE) staining of abdominal lymph-node metastasis from the primary ACC, showing polymorphic cells with wide eosinophil dense cytoplasm, atypical central nucleus of variable size and with chromatin, and no evident organoid growth pattern. Mitoses were very frequent and often atypical (mitotic index > 20 × 10 high-power field); necrotic areas and vascular tumor cell invasion were also frequent. B) HE staining of a skin metastasis from the second ACC recurrence, showing monomorphism of the tumor cell population with a nodular growth pattern simulating an organoid structure. The neoplastic cells had large eosinophilic cytoplasm, but this was more regular than in the primary ACC and first recurrence, and nuclei were less variable in size and chromatin distribution. Mitosis was found, but necrosis was absent. Analysis of α-inhibin expression by the use of anti-α-inhibin antibody (Serotec Ltd, Oxford, UK; 1:50) demonstrated positive staining in these second metastatic cells (C), but not in the primary ACC and first recurrence. Representation of steroidogenic enzyme expression in ACC specimens as determined by real-time quantitative RT–PCR and DNA microarray analysis (D and E). Comparisons between (D) primary ACC and normal adrenal cortex, (E) second ACC recurrence and normal adrenal cortex, and (F) second recurrence and primary ACC. Genes showing at least a twofold difference in expression between samples were considered under- or overexpressed. Upregulated genes are represented as red boxes; downregulated genes as green boxes; no significant differential expression as yellow boxes. Results are consistent with the prevalence of the aldosterone biosynthetic pathway in the primary ACC and a shift to the androgen and gluocorticoid biosynthetic pathway in the second ACC relapse.

Citation: European Journal of Endocrinology eur j endocrinol 153, 5; 10.1530/eje.1.02011

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    Plasma aldosterone and cortisol levels in a patient with ACC during the course of his disease. The red hatching indicates normal values; vertical hatching, upright plasma aldosterone, 140–830 pmol/l; horizontal hatching, plasma cortisol at 0800 h, 138–550 nmol/l. Mitotane doses are reported in grams per day; EDP: etoposide, doxorubicin, cisplatin; IG: irinotecan, gemcitabine.

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    Pathologic examination of ACC specimens (A–C): A) hematoxylin and eosin (HE) staining of abdominal lymph-node metastasis from the primary ACC, showing polymorphic cells with wide eosinophil dense cytoplasm, atypical central nucleus of variable size and with chromatin, and no evident organoid growth pattern. Mitoses were very frequent and often atypical (mitotic index > 20 × 10 high-power field); necrotic areas and vascular tumor cell invasion were also frequent. B) HE staining of a skin metastasis from the second ACC recurrence, showing monomorphism of the tumor cell population with a nodular growth pattern simulating an organoid structure. The neoplastic cells had large eosinophilic cytoplasm, but this was more regular than in the primary ACC and first recurrence, and nuclei were less variable in size and chromatin distribution. Mitosis was found, but necrosis was absent. Analysis of α-inhibin expression by the use of anti-α-inhibin antibody (Serotec Ltd, Oxford, UK; 1:50) demonstrated positive staining in these second metastatic cells (C), but not in the primary ACC and first recurrence. Representation of steroidogenic enzyme expression in ACC specimens as determined by real-time quantitative RT–PCR and DNA microarray analysis (D and E). Comparisons between (D) primary ACC and normal adrenal cortex, (E) second ACC recurrence and normal adrenal cortex, and (F) second recurrence and primary ACC. Genes showing at least a twofold difference in expression between samples were considered under- or overexpressed. Upregulated genes are represented as red boxes; downregulated genes as green boxes; no significant differential expression as yellow boxes. Results are consistent with the prevalence of the aldosterone biosynthetic pathway in the primary ACC and a shift to the androgen and gluocorticoid biosynthetic pathway in the second ACC relapse.

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