Scientific letter
Corticotropin secreting pancreatic neuroendocrine tumour, a therapeutic management challenge. A presentation of 2 cases
Tumor neuroendocrino pancreático secretor de corticotropina, un reto en el manejo terapéutico. A propósito de 2 casos
a Servicio de Endocrinología y Nutrición, Hospital Universitari de Bellvitge (HUB), l’Hospitalet de Llobregat, Barcelona, Spain
b Unidad Funcional de Nutrición Clínica, Institut Català d’Oncologia (ICO), l’Hospitalet de Llobregat, Barcelona, Spain
c Instituto de Investigación Biomédica de Bellvitge (IDIBELL), l’Hospitalet de Llobregat, Barcelona, Spain
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A presentation of 2 cases" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "204" "paginaFinal" => "206" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Andreu Simó-Servat, Inma Peiró, Carles Villabona" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Andreu" "apellidos" => "Simó-Servat" "email" => array:1 [ 0 => "andreusimoservat@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Inma" "apellidos" => "Peiró" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Carles" "apellidos" => "Villabona" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital Universitari de Bellvitge (HUB), l’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad Funcional de Nutrición Clínica, Institut Català d’Oncologia (ICO), l’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Instituto de Investigación Biomédica de Bellvitge (IDIBELL), l’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tumor neuroendocrino pancreático secretor de corticotropina, un reto en el manejo terapéutico. A propósito de 2 casos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1997 "Ancho" => 2943 "Tamanyo" => 385180 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course of the laboratory test findings corresponding to chromogranin and ACTH, with the treatment regimens in both described cases. 5-FU: 5-fluorouracil; RA: right adrenal gland; STZ: streptozocin; TKI: tyrosine kinase inhibitors; NR: normal range; CE: chemoembolization.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Functioning pancreatic neuroendocrine tumours (pNETs) account for 1% of all pancreatic neoplasms. Tumours of this kind that produce ACTH are even less frequent, representing 15% of the causes of ectopic ACTH secretion.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">1–3</span></a> They exhibit aggressive behavior and are mostly well differentiated (94%).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> When surgery is not possible, few effective therapeutic strategies are available against such tumours.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">4</span></a> Their management thus remains a challenge. We present our experience with a case of an initially non-functioning pNET that led to the development of Cushing's syndrome (CS) three years after the diagnosis, and a second case initially manifesting with evident CS.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Case 1</span><p id="par0010" class="elsevierStylePara elsevierViewall">A 57-year-old male was diagnosed in 2011 with well-differentiated pNET measuring 2<span class="elsevierStyleHsp" style=""></span>cm in size in the tail of the pancreas (pT2N0, grade 2 with Ki67 15%) and subjected to subtotal pancreatectomy and splenectomy, with no signs of CS. In December 2012, he suffered local recurrence and liver metastases. In June 2013, enucleation of the pancreatic head and liver radiofrequency ablation or alcoholization was performed, according to the type of lesion. However, due to hepatic progression of the disease, lanreotide was started in October 2013 (120<span class="elsevierStyleHsp" style=""></span>mg/28<span class="elsevierStyleHsp" style=""></span>days), together with spironolactone in view of a tendency toward hypertension (50<span class="elsevierStyleHsp" style=""></span>mg/day). In October 2014, due to hepatic progression, lanreotide was replaced by everolimus 10<span class="elsevierStyleHsp" style=""></span>mg/day, administered from February 2015 to March 2016, with a partial response. In parallel, in November 2014 the patient developed paraneoplastic CS with a worsening general condition, asthenia, myopathy, anasarca, diabetes mellitus, hypertensive crisis, bilateral pulmonary thromboembolism and severe hypokalemia (2.19.<span class="elsevierStyleHsp" style=""></span>mmol/l) with metabolic alkalosis. The physical examination revealed facial flushing and hyperpigmentation. Plasma ACTH was 122<span class="elsevierStyleHsp" style=""></span>pg/ml [normal range (NR): 10–60], with serum cortisol 29.5<span class="elsevierStyleHsp" style=""></span>μg/dl [NR: 10–25] and urinary free cortisol (UFC) 143.8<span class="elsevierStyleHsp" style=""></span>μg/day [NR: 20–100]. Computed tomography (CT) showed bilateral adrenal gland hyperplasia. In view of these findings, ketoconazole was started but subsequently replaced by metyrapone due to toxic hepatitis (2000–4000<span class="elsevierStyleHsp" style=""></span>mg/day). Because of poor control of hypercortisolism, in September 2016 embolization was performed, but only of the left adrenal gland due to problems with vascular access to the right gland, with a subsequent persistence of high ACTH (970<span class="elsevierStyleHsp" style=""></span>pg/ml) and plasma cortisol levels (63.3<span class="elsevierStyleHsp" style=""></span>μg/dl). In addition, in April and July 2016 chemoembolization (CE) was indicated in two sessions due to metastatic liver progression. Radiologically, signs of liver disease progression continued and a metastatic lytic lesion appeared in L1. A tyrosine kinase inhibitor (lenvatinib) was started in February 2017, with a partial response. The CT study in January 2018 showed the tumour with no radiographic progression but with an elevated ACTH concentration of 676<span class="elsevierStyleHsp" style=""></span>pg/ml, serum cortisol 25.6<span class="elsevierStyleHsp" style=""></span>μg/dl and UFC 766.7<span class="elsevierStyleHsp" style=""></span>μg/day, under treatment with lenvatinib and metyrapone.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Case 2</span><p id="par0015" class="elsevierStylePara elsevierViewall">A 50-year-old woman was diagnosed with CS in 2014 secondary to ectopic ACTH secretion due to a well-differentiated pNET (grade 2, with Ki67 15%), and non-resectable liver metastases. She suffered from postural instability, asthenia and proximal muscle weakness. The physical examination revealed abdominal bloating, hyperpigmentation, hirsutism, and acne. The laboratory tests revealed a plasma ACTH concentration of 1085<span class="elsevierStyleHsp" style=""></span>pg/ml, serum cortisol 30<span class="elsevierStyleHsp" style=""></span>μg/dl and UFC 3900<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h, with no evidence of slowing in low and high dose dexamethasone suppression testing. The CT scan revealed a solid tumour in the isthmus-head of the pancreas, with liver dissemination. Scintigraphy for somatostatin receptors proved positive in the head of the pancreas. Chemoembolization of the metastases was performed, a stent was placed in the portal vein, and ketoconazole and spironolactone were started for the control of CS. However, a plasma ACTH level of 758.34<span class="elsevierStyleHsp" style=""></span>pg/ml persisted, with UFC 664<span class="elsevierStyleHsp" style=""></span>μg/day, and bilateral adrenalectomy was indicated (June 2015). In view of the above, in January 2016 chemotherapy (streptozocin and 5-fluorouracil) was started, ending in April due to liver progression after three cycles. Sunitinib (37.5<span class="elsevierStyleHsp" style=""></span>g/day) was started in May.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The CT scan in January 2018 showed no evidence of radiographic progression, but ACTH remained high (4700<span class="elsevierStyleHsp" style=""></span>pg/ml), with UFC 132<span class="elsevierStyleHsp" style=""></span>μg/day under replacement therapy with hydrocortisone and fludrocortisone.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of treatment in non-resectable ACTH-secreting pNETs is biochemical control of CS and the prevention of disease progression.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a> Serum chromogranin is the general biochemical marker for monitoring tumour progression. However, when the tumour is functional, the excess hormone is also a progression marker. Thus, in the rare cases of pNETs that produce ACTH, as in our patients, a parallel relationship is observed between the ACTH and chromogranin levels, depending on the functionality of the tumour (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Inadequate control of hypercortisolism is indicative of a poor prognosis.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">2,3,6</span></a> It is advisable to control this alteration before treatment is started. In tumours expressing SSTR-2 and SSTR-5, somatostatin analogs are a therapeutic strategy for stabilizing tumour growth and lowering hormone secretion.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a> Another therapeutic option for hypercortisolemia is metyrapone or ketoconazole, as well as bilateral adrenalectomy, which has been shown to improve survival in the first two years,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> as in our second case. In the case of disease progression in non-resectable advanced cancer, everolimus and sunitinib,<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">6,7</span></a> and even lenvatinib, are new and promising options, though there is little long-term experience with these drugs. Everolimus was used in the first case without success, while sunitinib in the second patient resulted in disease stabilization. Traditional chemotherapy with streptozocin and 5-fluorouracil is an option, but proved unsuccessful in the second case. Radionuclide therapy may be effective when SRS or 68Ga-DOTA-peptide-PET/CT are positive.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">2,3</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Change in functionality due to tumour cell pluripotency makes management difficult. In the first initially non-functioning case, ACTH hyperfunction developed after three years, and repeat histological study of the metastatic foci proved helpful in defining the biological behavior of the tumour.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">It can be concluded that evidence-based treatment decisions are lacking for ACTH-secreting pNETs. In the described cases, treatment changes were made without a fully effective response. Randomized clinical trials are needed to establish the best treatment options, since short case series such as our own are currently the only source of scientific evidence.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">3,4</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors state that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Case 2" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Simó-Servat A, Peiró I, Villabona C. Tumor neuroendocrino pancreático secretor de corticotropina, un reto en el manejo terapéutico. A propósito de 2 casos. Endocrinol Diabetes Nutr. 2019;66:204–206.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1997 "Ancho" => 2943 "Tamanyo" => 385180 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course of the laboratory test findings corresponding to chromogranin and ACTH, with the treatment regimens in both described cases. 5-FU: 5-fluorouracil; RA: right adrenal gland; STZ: streptozocin; TKI: tyrosine kinase inhibitors; NR: normal range; CE: chemoembolization.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 0 | 7 |
| 2024 October | 11 | 0 | 11 |
| 2024 September | 9 | 4 | 13 |
| 2024 August | 13 | 3 | 16 |
| 2024 July | 24 | 5 | 29 |
| 2024 June | 16 | 6 | 22 |
| 2024 May | 9 | 3 | 12 |
| 2024 April | 22 | 9 | 31 |
| 2024 March | 14 | 6 | 20 |
| 2024 February | 17 | 6 | 23 |
| 2024 January | 18 | 4 | 22 |
| 2023 December | 16 | 17 | 33 |
| 2023 November | 16 | 5 | 21 |
| 2023 October | 20 | 11 | 31 |
| 2023 September | 10 | 0 | 10 |
| 2023 August | 17 | 3 | 20 |
| 2023 July | 9 | 3 | 12 |
| 2023 June | 21 | 6 | 27 |
| 2023 May | 32 | 1 | 33 |
| 2023 April | 45 | 2 | 47 |
| 2023 March | 24 | 3 | 27 |
| 2023 February | 25 | 3 | 28 |
| 2023 January | 11 | 5 | 16 |
| 2022 December | 13 | 3 | 16 |
| 2022 November | 13 | 7 | 20 |
| 2022 October | 14 | 8 | 22 |
| 2022 September | 17 | 9 | 26 |
| 2022 August | 16 | 9 | 25 |
| 2022 July | 11 | 4 | 15 |
| 2022 June | 9 | 8 | 17 |
| 2022 May | 15 | 5 | 20 |
| 2022 April | 11 | 9 | 20 |
| 2022 March | 19 | 4 | 23 |
| 2022 February | 10 | 4 | 14 |
| 2022 January | 11 | 5 | 16 |
| 2021 December | 36 | 5 | 41 |
| 2021 November | 12 | 8 | 20 |
| 2021 October | 10 | 8 | 18 |
| 2021 September | 10 | 10 | 20 |
| 2021 August | 6 | 6 | 12 |
| 2021 July | 7 | 7 | 14 |
| 2021 June | 11 | 6 | 17 |
| 2021 May | 17 | 14 | 31 |
| 2021 April | 20 | 20 | 40 |
| 2021 March | 25 | 6 | 31 |
| 2021 February | 24 | 5 | 29 |
| 2021 January | 19 | 9 | 28 |
| 2020 December | 21 | 10 | 31 |
| 2020 November | 13 | 5 | 18 |
| 2020 October | 12 | 6 | 18 |
| 2020 September | 7 | 10 | 17 |
| 2020 August | 14 | 7 | 21 |
| 2020 July | 9 | 9 | 18 |
| 2020 June | 13 | 3 | 16 |
| 2020 May | 13 | 7 | 20 |
| 2020 April | 7 | 1 | 8 |
| 2020 March | 13 | 5 | 18 |
| 2020 February | 11 | 1 | 12 |
| 2020 January | 18 | 7 | 25 |
| 2019 December | 6 | 3 | 9 |
| 2019 November | 6 | 0 | 6 |
| 2019 October | 4 | 0 | 4 |
| 2019 September | 4 | 2 | 6 |
Show all
