Scientific letter
Adrenal carcinoma: A retrospective analysis of our series
Carcinoma adrenal: análisis retrospectivo de nuestra serie
Paula Andujara, Jose Manuel Cabezas-Agrícolaa,
, Jose Manuel Cameselle-Teijeirob, Francisco Barón-Duartec, Ignacio Bernabeua, Felipe F. Casanuevaa
Corresponding author
a Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain
b Servicio de Anatomía Patológica, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain
c Servicio de Oncología Médica, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain
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AC shows an aggressive behavior, with a survival in metastatic disease less than 10% at 5 years and 32–48% in patients who underwent complete resection,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> which is the treatment of choice.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We present 7 patients with AC treated in our hospital between 1993 and 2010, whose clinical and histological characteristics and treatment received are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">AC is usually a sporadic tumor, but it may appear in familial syndromes such as Li-Fraumeni syndrome, Gardner syndrome, multiple endocrine neoplasia 1, Carney complex or neurofibromatosis type 1 (NF-1). Until 2005 only four cases of AC associated with NF-1 had been described.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> They are usually functioning tumors (∼60%) and Cushing's syndrome is the most frequent (45%); functioning tumors can present with Cushing and androgens overproduction (30%) or with virilization alone (10%).<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The overproduction of mineralocorticoids is uncommon<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>; it causes hypertension and hypokalemia and is generally associated with an aggressive behavior,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> as in our case 6. Patients with non-functioning tumors may have abdominal pain or may be detected as incidentalomas.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In fact, in a review of Barzon et al., ACs represent 4.4% of adrenal incidentalomas.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Survival depends on the stage: at 5 years it is 82% for stage I, 61% in stage II, 50%in stage III and 13% in stage IV, according to staging of ENSAT 2008.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This classification has a superior prognostic value than the UICC staging system.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Other factors associated with poor prognosis are: advanced age, hypersecretion of cortisol, tumor size and a high Ki67 proliferation index.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,8</span></a> Other molecular markers have been proposed as IGF2 gene and IGF1 receptor gene and more recently the steroidogenic factor 1 (SF-1) (transcription factor associated with the development and synthesis of steroidogenic tissues) which has been correlated with a poorer prognosis.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Complete resection is the only curative option and the most important prognostic factor, especially in stages I–III.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> There is not a standard type of surgery, but some of the authors<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> suggest that to reduce local recurrence and improve disease-free survival and overall survival, adrenalectomy should be accompanied by regional lymphadenectomy (including celiac, renal hilum and ipsilateral lateroaortic ganglia). The technique of choice for adrenalectomy is open surgery, although some of the authors propose laparoscopic surgery for tumors<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>cm without evidence of invasive disease; but this surgery should only be performed by experienced surgeons.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> In stage IV, cytoreductive surgery can be considered for hormonal control and/or to facilitate radiofrequency ablation.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Radiotherapy (RDT) has traditionally been considered ineffective in AC. However, a retrospective study of 58 patients showed that adjuvant RDT significantly reduced the risk of local recurrence (but not affected overall survival).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Some of the authors recommend adjuvant RDT for AC in patients with (1) macroscopic incomplete (R1) or uncertain (Rx) resection, (2) in patients with stage III or (3) in tumors with complete resection (R0), size<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>cm, vascular invasion and Ki67<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10%.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> RDT may also be beneficial when surgery is not feasible. These recommendations are recent, so none of our patients received RDT.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Mitotane is an inhibitor of the cortisol synthesis and an adrenal cytotoxic agent. Its use as adjuvant therapy after surgery has been controversial because there are no randomized studies, but it is the only drug formally approved for AC. A retrospective nonrandomized multicenter study<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> showed that adjuvant mitotane was associated with a lower recurrence rate (49% in the German mitotane group versus 73% in the Italian and 91% in the German non-mitotane groups). After this study, an international panel of experts<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> proposed administration of adjuvant mitotane in patients with R1 or Rx and/or Ki67<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10%, but it would not be mandatory in the following situations: stage I or II (classification ENSAT 2008), radical resection R0 and Ki67<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>10%. There is an ongoing multinational randomized trial comparing adjuvant treatment with mitotane versus only monitoring (ADIUVO trial) for patients with low/moderate recurrence risk (stages I–III without residual microscopic disease). Side effects of mitotane may limit its use, the most frequent being neurological and gastrointestinal. There is no consensus on the duration of treatment, but it varies between 2 and 5 years. The initial dose could be 1–2<span class="elsevierStyleHsp" style=""></span>g/day and it should be increased gradually, and according to tolerability, to obtain plasma levels between 14 and 20<span class="elsevierStyleHsp" style=""></span>mg/L,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> values that are predictors of greater therapeutic response. Some of the authors propose an initial dose of 4–6<span class="elsevierStyleHsp" style=""></span>g/day.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Mitotane can induce adrenal insufficiency, so replacement therapy with hydrocortisone is necessary. A dose of 50<span class="elsevierStyleHsp" style=""></span>mg/day may be required.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">There are some factors that seem to influence the response to mitotane. Volante et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> have found that RRM1 (ribonucleotide reductase large subunit 1) gene expression is associated with mitotane response: in patients with a low gene expression, adjuvant mitotane showed an improved disease-free survival but it did not occur with a high RRM1 expression.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Most of our patients received mitotane generally for short periods (maximum 6 months) because of adverse neurological effects, or sudden death in the days after the surgery (case 2) or because it was diagnosed initially as pheochromocytoma (case 7).</p><p id="par0050" class="elsevierStylePara elsevierViewall">If there is hypercortisolism, mitotane must be combined with fast-acting drugs, because of its slowness to reach therapeutic levels such as ketoconazole (or metyrapone) or, if oral intolerance, intravenous etomidate.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Chemotherapy (QMT) is reserved for advanced CA in progression despite mitotane. Recently, the result of the first randomized international trial, the FIRM-ACT,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> which compared the two more frequently used antineoplastic regimens, has been published. The results showed that the combination of mitotane with etoposide, doxorubicin and cisplatin (M-EDP) achieved a greater objective tumor response rate than the combination of mitotane with streptozotocin (23% versus 9%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001), an increase in free survival progression also significant (5.3 months versus 2, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) and a higher percentage of patients without progression within 12 months (26% versus 7%). However, overall survival was no significantly different between both groups (14.8 months in M-EDP group versus 12 in patients with mitotane and streptozotocin, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.07), although these results could be influenced by the change of therapy in case of if progression.</p><p id="par0060" class="elsevierStylePara elsevierViewall">If these two regimens fail, then salvage treatment with gemcitabine and metronomic fluoropyrimidines (fluorouracil intravenous or oral capecitabine) is recommended. This option has showed stabilization of the disease. Another treatment that has been proposed is capecitabine with the monoclonal antibody against VEGF (Vascular Endothelial Growth Factor) bevacizumab, but the results have been unsatisfactory.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In our series, only two cases were treated with QMT and they achieved a longer survival (cases 3 and 5). Cases 2 and 6 died prematurely, cases 1 and 4 were seen before 1998, the year when M-EDP regimen was published and case 7 was initially diagnosed as malignant pheochromocytoma. Sometimes, the histopathological differential diagnosis between malignant pheochromocytoma and AC is difficult and the inmunohistochemical study is necessary. The tumor cell positivity for inhibin, melan A and calretinin suggests adrenal cortical tumor, while chromogranin A is only positive in pheochromocytoma.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In recent years, different antineoplastic targeted drugs (imatinib, gefitinib, sorafenib) have been tested with poor results. The best results, although modest, were obtained with antiangiogenic multikinase inhibitor sunitinib (SU). In a recent phase II trial in refractory CA, SU achieved stable disease in 5 out of 35 patients, although these results could be negatively influenced by the inducing effect on cytochrome p450-3A4 of mitotane, causing lower plasma levels of SU and therefore, less effectiveness.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Other future therapeutic option is radiopharmaceutical therapy with iodine-metomidate (<span class="elsevierStyleSup">131</span>I-IMTO), which is very selective for adrenocortical tissue. In patients with advanced ACC when radical surgery is not possible and the uptake of <span class="elsevierStyleSup">131</span>I-IMTO is high, it has been seen that in patients who respond to treatment, median progression-free survival is 14 months.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Other options are IGF-1R inhibitors and SF-1 inhibitors.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">dx: diagnosis; F: female; M: male; NF-1: neurofibromatosis 1; UFC: urinary free cortisol; T: testosterone; ICV: inferior cava vein; QMT: chemotherapy; OA: open adrenalectomy.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Case \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sex/age at dx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Functionality/reason for consultation/associated disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Hormonal studies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Size/weight \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Ki67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Weiss Index<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TMN at diagnosis/metastasis site \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Survival (months) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F/65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cushing/Cushing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UFC: 1150<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h (40–285) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8<span class="elsevierStyleHsp" style=""></span>cm/197<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II/liver, peritoneum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA Mitotane \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F/74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cushing<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>virilization/incidentaloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UFC: 1100<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h Androstendione: 8.37<span class="elsevierStyleHsp" style=""></span>ng/mL (0.9–3.1) T: 4.4<span class="elsevierStyleHsp" style=""></span>pg/mL (0.7–3.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12<span class="elsevierStyleHsp" style=""></span>cm/386<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II/No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F/40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Virilization/incidentaloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T: 2.36<span class="elsevierStyleHsp" style=""></span>ng/mL (0.7–3.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.5<span class="elsevierStyleHsp" style=""></span>cm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II/lung, liver, brain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA Mitotane QMT (Cisplatin 2001. Capecitabine<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>Streptozotocin 2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">132 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No/incidentaloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14<span class="elsevierStyleHsp" style=""></span>cm/727<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III/ICV thrombosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cushing/incidentaloma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UFC: 684<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h (40–285) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16<span class="elsevierStyleHsp" style=""></span>cm/570<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III/liver, small intestine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA QMT (Cisplatin<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>5-fuorouracil) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M/59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperaldosteronism/hypertension<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>hypokalemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aldosterone<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2000<span class="elsevierStyleHsp" style=""></span>pg/mL (0–200) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.5<span class="elsevierStyleHsp" style=""></span>cm/495<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV/lung \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA Mitotane \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F/42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No/incidentaloma/NF-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.5<span class="elsevierStyleHsp" style=""></span>cm/439<span class="elsevierStyleHsp" style=""></span>g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II/liver, ICV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab422949.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patients characteristics.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of patients with adrenal cancer: recommendations of an international consensus conference" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.E. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 16 | 1 | 17 |
| 2024 September | 27 | 5 | 32 |
| 2024 August | 29 | 8 | 37 |
| 2024 July | 22 | 2 | 24 |
| 2024 June | 17 | 5 | 22 |
| 2024 May | 17 | 6 | 23 |
| 2024 April | 16 | 8 | 24 |
| 2024 March | 22 | 3 | 25 |
| 2024 February | 16 | 8 | 24 |
| 2024 January | 16 | 3 | 19 |
| 2023 December | 17 | 8 | 25 |
| 2023 November | 17 | 5 | 22 |
| 2023 October | 18 | 11 | 29 |
| 2023 September | 25 | 7 | 32 |
| 2023 August | 13 | 5 | 18 |
| 2023 July | 12 | 3 | 15 |
| 2023 June | 16 | 3 | 19 |
| 2023 May | 15 | 9 | 24 |
| 2023 April | 5 | 3 | 8 |
| 2023 March | 16 | 6 | 22 |
| 2023 February | 12 | 8 | 20 |
| 2023 January | 9 | 3 | 12 |
| 2022 December | 18 | 15 | 33 |
| 2022 November | 19 | 7 | 26 |
| 2022 October | 24 | 9 | 33 |
| 2022 September | 18 | 6 | 24 |
| 2022 August | 18 | 9 | 27 |
| 2022 July | 22 | 11 | 33 |
| 2022 June | 14 | 7 | 21 |
| 2022 May | 43 | 9 | 52 |
| 2022 April | 25 | 9 | 34 |
| 2022 March | 40 | 12 | 52 |
| 2022 February | 25 | 8 | 33 |
| 2022 January | 36 | 10 | 46 |
| 2021 December | 17 | 13 | 30 |
| 2021 November | 16 | 11 | 27 |
| 2021 October | 17 | 18 | 35 |
| 2021 September | 18 | 11 | 29 |
| 2021 August | 25 | 10 | 35 |
| 2021 July | 24 | 13 | 37 |
| 2021 June | 13 | 6 | 19 |
| 2021 May | 18 | 9 | 27 |
| 2021 April | 30 | 15 | 45 |
| 2021 March | 32 | 7 | 39 |
| 2021 February | 7 | 5 | 12 |
| 2021 January | 14 | 14 | 28 |
| 2020 December | 15 | 12 | 27 |
| 2020 November | 17 | 13 | 30 |
| 2020 October | 10 | 6 | 16 |
| 2020 September | 22 | 10 | 32 |
| 2020 August | 15 | 10 | 25 |
| 2020 July | 25 | 17 | 42 |
| 2020 June | 20 | 13 | 33 |
| 2020 May | 24 | 13 | 37 |
| 2020 April | 20 | 8 | 28 |
| 2020 March | 27 | 8 | 35 |
| 2020 February | 33 | 4 | 37 |
| 2020 January | 29 | 5 | 34 |
| 2019 December | 31 | 16 | 47 |
| 2019 November | 20 | 8 | 28 |
| 2019 October | 17 | 15 | 32 |
| 2019 September | 18 | 6 | 24 |
| 2019 August | 16 | 4 | 20 |
| 2019 July | 22 | 16 | 38 |
| 2019 June | 17 | 15 | 32 |
| 2019 May | 52 | 18 | 70 |
| 2019 April | 17 | 26 | 43 |
| 2019 March | 9 | 4 | 13 |
| 2019 February | 9 | 10 | 19 |
| 2019 January | 18 | 8 | 26 |
| 2018 December | 5 | 6 | 11 |
| 2018 November | 12 | 4 | 16 |
| 2018 October | 15 | 4 | 19 |
| 2018 September | 9 | 3 | 12 |
| 2018 August | 5 | 5 | 10 |
| 2018 July | 4 | 2 | 6 |
| 2018 June | 2 | 3 | 5 |
| 2018 May | 7 | 1 | 8 |
| 2018 April | 3 | 3 | 6 |
| 2018 March | 6 | 2 | 8 |
| 2018 February | 6 | 2 | 8 |
| 2018 January | 7 | 4 | 11 |
| 2017 December | 8 | 6 | 14 |
| 2017 November | 10 | 3 | 13 |
| 2017 October | 12 | 8 | 20 |
| 2017 September | 7 | 3 | 10 |
| 2017 August | 16 | 2 | 18 |
| 2017 July | 7 | 4 | 11 |
| 2017 June | 10 | 6 | 16 |
| 2017 May | 15 | 2 | 17 |
| 2017 April | 26 | 4 | 30 |
| 2017 March | 22 | 24 | 46 |
| 2017 February | 18 | 1 | 19 |
| 2017 January | 11 | 0 | 11 |
| 2016 December | 13 | 6 | 19 |
| 2016 November | 17 | 3 | 20 |
| 2016 October | 54 | 7 | 61 |
| 2016 September | 41 | 4 | 45 |
| 2016 August | 14 | 2 | 16 |
| 2016 July | 26 | 4 | 30 |
| 2016 June | 41 | 3 | 44 |
| 2016 May | 25 | 6 | 31 |
| 2016 April | 38 | 7 | 45 |
| 2016 March | 24 | 9 | 33 |
| 2016 February | 26 | 10 | 36 |
| 2016 January | 15 | 8 | 23 |
| 2015 December | 27 | 10 | 37 |
| 2015 November | 28 | 5 | 33 |
| 2015 September | 0 | 1 | 1 |
| 2015 July | 1 | 2 | 3 |
| 2015 February | 1 | 0 | 1 |
| 2014 December | 0 | 1 | 1 |
| 2014 November | 1 | 0 | 1 |
| 2014 May | 1 | 0 | 1 |
| 2014 April | 0 | 1 | 1 |
| 2014 March | 22 | 8 | 30 |
| 2014 February | 23 | 17 | 40 |
| 2014 January | 23 | 7 | 30 |
| 2013 December | 14 | 5 | 19 |
| 2013 November | 17 | 5 | 22 |
Show all
