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CASE REPORT |
Department of Histology, Microbiology and Medical Biotechnologies, University of Padova,Via A. Gabelli 63, I-35121 Padova, Italy 1 Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy and 2 Departments of Pathology and 3 Medical and Surgical Sciences, University of Padova,Via A. Gabelli 63, I-35121 Padova, Italy
(Correspondence should be addressed to L Barzon; Email: luisa.barzon{at}unipd.it)
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-
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 x 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).
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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 (1–3), 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).
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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 -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 17-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.
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-subunit in the cortisol-producing ACC recurrence (Fig. 2C) could have also contributed to the shift from mineralocorticoid to glucorticoid formation. The inhibin -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 -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.
References
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