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Concurrent corticotroph pituitary tumor and granular cell tumor: A very uncommon association
Doble tumor hipofisario corticotropo-tumor de células granulares: una asociación muy infrecuente
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López-Muñoz, Sandra Silva Ortega, Ruth Sánchez Ortiga, Ignacio Aranda López, Antonio Picó Alfonso" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Beatriz" "apellidos" => "López-Muñoz" "email" => array:1 [ 0 => "bealopezmz@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Sandra" "apellidos" => "Silva Ortega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Ruth" "apellidos" => "Sánchez Ortiga" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Ignacio" "apellidos" => "Aranda López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Antonio" "apellidos" => "Picó Alfonso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Sección Endocrinología y Nutrición, Hospital General Universitario de Alicante-ISABIAL, Alicante, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Sección de Anatomía Patológica, Hospital General Universitario de Alicante-ISABIAL, Alicante, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Doble tumor hipofisario corticotropo-tumor de células granulares: una asociación muy infrecuente" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 493 "Ancho" => 1305 "Tamanyo" => 286256 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Histological study. A) Haematoxylin and eosin staining. B) Immunohistochemistry for ACTH.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Granular cell tumours (GCTs) belong to the group of posterior pituitary tumours (2017 WHO classification).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> They are rare tumours, with the common characteristic of having positive immunohistochemistry for thyroid transcription factor 1 (TTF-1), S-100 protein and vimentin. Coexistence with functioning pituitary adenomas is exceptional, with very few cases described to date.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> We describe the clinical case of a woman with a posterior pituitary GCT associated with Cushing's disease.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The patient was born in 1954 with a history of primary arterial hypertension, type 2 diabetes mellitus and right frontal meningioma. In 2014, she was diagnosed with Cushing’s syndrome as a result of changes in the facial phenotype, muscle hypotrophy, increased abdominal girth, spontaneous haematomas and rib fractures. She did not present with stretch marks. Her abdominal girth was 101 cm, weight 60.9 kg, height 154 cm and blood pressure 165/88 mmHg. The biochemical functional study suggested an endogenous hypercortisolism of pituitary origin [urinary free cortisol (UFC) 318 µg/g creatinine (Cr) (normal 10-100 µg/g Cr)]. However, the pituitary magnetic resonance was normal. A petrosal sinus catheterisation confirmed the pituitary origin of the hypercortisolism. It was decided to perform an endonasal endoscopic hemihypophysectomy in May 2016. During the surgical procedure, a normal pituitary was observed, but with a suspicious fibrous posterolateral area, which was resected. The anatomical pathology study reported the presence of a normal pituitary gland in one of the blocks. In the other, the presence of a fibrillar tumour composed of spindle cells, epithelioid cells and granular cells was observed, positive for S-100 protein and TTF-1, and compatible with GCT. Nests of cells positive for synaptophysin and ACTH were observed inside, concordant with a corticotropinoma (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The surgery was not curative (UFC 311.6 µg/g Cr two months after the intervention), so treatment with fractionated stereotaxic radiotherapy was decided on (accumulated dose of 51 Gy in 28 sessions) and adjuvant ketoconazole was started (800 mg every 24 hours) in July 2016. Despite the high doses of ketoconazole, it was not possible to normalise the concentrations of urinary free cortisol, so the ketoconazole was replaced with pasireotide 20 mg every 28 days. The pasireotide treatment normalised UFC concentrations (87 µg/g Cr) and significantly reduced circulating ACTH and serum cortisol concentrations, but the metabolic control of the patient's prior diabetes was impaired. After three years of treatment with pasireotide and four years after radiotherapy, the patient presented biochemical criteria of controlled disease, with significant clinical improvement. The current dose of pasireotide is 20 mg every six weeks. Diabetes is adequately controlled with sitagliptin 100 mg/day and dapagliflozin 10 mg/day.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The co-existence of functioning pituitary adenomas and posterior pituitary tumours is rare. In a recently published review,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> 10 cases of posterior pituitary tumours associated with hypercortisolism are described, seven of them with histology of pituicytomas and three with GCT. Updating the data reported by said review, at the time of writing this clinical case, there have been nine pituicytomas associated with Cushing's syndrome and only two GCTs, the one reported by Zhang et al.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and the current clinical case, already mentioned previously.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The discrepancy in the 2019 review with the aforementioned data is found in the three clinical cases reported by Feng et al.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>, which were in fact two pituicytomas (one associated with hypercortisolism and the other with acromegaly) and only one GCT, associated with acromegaly. The ninth case of pituicytoma associated with Cushing’s disease has recently been published.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> To date, there have been five cases of posterior pituitary tumours associated with acromegaly, two of them with GCT histology.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Guerrero et al.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> theorise that the existence of a posterior pituitary tumour could produce substances (cytokines, growth factors) that stimulate the proliferation of adenohypophysis cells, fostering the emergence of functioning adenohypophyseal tumours.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The clinical findings of neurohypophyseal tumours are indistinguishable from non-functioning pituitary macroadenomas, their presentation more frequently being visual disturbances (64%) or headache (33%).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Usually, a space-occupying lesion is observed on imaging tests, and the definitive diagnosis is obtained with the result of the pathological anatomy study. Histological findings are comparable to those described in the clinical case, but as a differential characteristic compared to pituicytomas and fusiform cell oncocytomas, GCTs are positive in periodic acid Schiff (PAS) staining.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">It is agreed that the treatment for this type of tumour should be surgical, preferably via the transsphenoidal route. Prognosis is dependent on complete resection.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Due to their anatomical location and greater tendency to bleed (they are more vascularised structures), the surgery is more complex than that performed for pituitary adenomas.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The present case describes a GCT with an infiltration of corticotropic cells, responsible for the hyperproduction of ACTH, without evidence of a sellar mass. Coincidentally, in the other case described of Cushing's syndrome and GCT<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> a tumour mass wasn't visualised on magnetic resonance either. However, biochemical control was achieved after the intervention. In the present case, use of radiotherapy was necessary as an adjuvant treatment to control hypercortisolism in the long term. Ketoconazole was used as medical treatment, without response, so it was decided to switch to pasireotide.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Pasireotide is the first agent with a direct effect on pituitary hormone secretion approved in the SmPC for the treatment of Cushing’s disease. It has a high affinity for the somatostatin receptor type 5 (SSTR5), which is strongly expressed in corticotropinomas, having shown normalisation and reduction of hypercortisolism in its pivotal studies.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In ‘real life’<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> a 68% biochemical normalisation of hypercortisolism is described in resistant or recurrent Cushing’s disease (previously treated with surgery, radiotherapy or medical treatment). This suggests that there must be one or more differential characteristics in the pasireotide-responsive tumour subgroup, perhaps a higher expression of SSTR5. It is possible that the suggested pathogenesis for the association of two contiguous but different gland tumours may explain the excellent response of ACTH hypersecretion to treatment with pasireotide seen in the case described. Obviously it would take a much larger series to reach a conclusion. Unfortunately, we do not have molecular data available on the expression of somatostatin receptors in this tumour, so it is not possible to establish a relationship with the response to pasireotide.</p><p id="par0045" class="elsevierStylePara elsevierViewall">We present the case of a patient with GCT with corticotropic cell nests in its interior responsible for Cushing’s disease with excellent response to treatment with pasireotide.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical considerations</span><p id="par0050" class="elsevierStylePara elsevierViewall">Informed consent is obtained from all patients operated on for pituitary disease at our centre, whereby they agree to the inclusion of their samples in the biobank and the use of their anonymised clinical data in scientific dissemination.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => 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: López-Muñoz B, Silva Ortega S, Sánchez Ortiga R, Aranda López I, Picó Alfonso A. Doble tumor hipofisario corticotropo-tumor de células granulares: una asociación muy infrecuente. Endocrinol Diabetes Nutr. 2021;68:591–593.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 493 "Ancho" => 1305 "Tamanyo" => 286256 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Histological study. A) Haematoxylin and eosin staining. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 0 | 1 |
| 2024 October | 7 | 1 | 8 |
| 2024 September | 13 | 16 | 29 |
| 2024 August | 10 | 2 | 12 |
| 2024 July | 18 | 2 | 20 |
| 2024 June | 12 | 3 | 15 |
| 2024 May | 12 | 2 | 14 |
| 2024 April | 48 | 1 | 49 |
| 2024 March | 18 | 3 | 21 |
| 2024 February | 20 | 2 | 22 |
| 2024 January | 13 | 1 | 14 |
| 2023 December | 22 | 2 | 24 |
| 2023 November | 7 | 1 | 8 |
| 2023 October | 8 | 4 | 12 |
| 2023 September | 4 | 0 | 4 |
| 2023 August | 10 | 0 | 10 |
| 2023 July | 8 | 1 | 9 |
| 2023 June | 17 | 1 | 18 |
| 2023 May | 40 | 1 | 41 |
| 2023 April | 34 | 1 | 35 |
| 2023 March | 30 | 0 | 30 |
| 2023 February | 16 | 4 | 20 |
| 2023 January | 5 | 1 | 6 |
| 2022 December | 13 | 3 | 16 |
| 2022 November | 6 | 4 | 10 |
| 2022 October | 6 | 5 | 11 |
| 2022 September | 6 | 7 | 13 |
| 2022 August | 9 | 3 | 12 |
| 2022 July | 12 | 10 | 22 |
| 2022 June | 9 | 4 | 13 |
| 2022 May | 7 | 6 | 13 |
| 2022 April | 8 | 5 | 13 |
| 2022 March | 0 | 2 | 2 |
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