Letter to the Editor
Atypical presentation of medullary thyroid carcinoma
Carcinoma medular de tiroides de presentación atípica
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In approximately 25% of cases, MTC occurs in the context of multiple endocrine neoplasm type 2 (MEN 2) caused by RET germline mutations. Up to 65% of patients with sporadic disease have somatic RET mutations.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In addition to calcitonin and carcinoembryonic antigen, C cells can also ectopically secrete corticotropin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH). Cushing's syndrome due to MTC-induced ectopic secretion of CRH or ACTH is rare and data on clinical features, treatment and outcome are limited and are mostly from case studies. Cushing's syndrome occurs mainly in metastatic cases and significantly worsens the prognosis: about 50% of mortality has been attributed to complications of hypercortisolism.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We report the case of a 43-year-old male, whose history of interest included a fracture of the T6–T8 vertebral bodies 2 years earlier and a fracture of the right hip 1<span class="elsevierStyleHsp" style=""></span>year ago. Bone densitometry showed osteoporosis. He was being treated with teriparatide 20<span class="elsevierStyleHsp" style=""></span>mg daily, calcium carbonate 2.5<span class="elsevierStyleHsp" style=""></span>g/cholecalciferol 800 IU.</p><p id="par0020" class="elsevierStylePara elsevierViewall">He was admitted to hospital due to worsening pain, and on examination he had facial plethora, abdominal obesity and muscular atrophy. In view of the suspicion of Cushing's disease, laboratory tests were requested, highlighting ACTH 114<span class="elsevierStyleHsp" style=""></span>pg/mL (5–50<span class="elsevierStyleHsp" style=""></span>pg/mL), cortisol 43.2 mcg/dl (5–25<span class="elsevierStyleHsp" style=""></span>mcg/dl), urinary free cortisol 24<span class="elsevierStyleHsp" style=""></span>h 516<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h (0–180<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h), suppression test with 1<span class="elsevierStyleHsp" style=""></span>mg dexamethasone: 17mcg/dl (<1.8 mcg/dl).</p><p id="par0025" class="elsevierStylePara elsevierViewall">A pituitary MRI scan was performed and no pituitary adenoma was observed. The study was completed with a CT scan of the chest and abdomen showing: pathological lymphadenopathies in the upper mediastinum, enlargement of the thyroid with a nodular image in the right lobe and multiple involvement of the vertebrae and posterior costal curvature. Both adrenals were enlarged in the abdomen with no nodules.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The study was completed with thyroid ultrasound: a 4<span class="elsevierStyleHsp" style=""></span>cm nodule with lobulated borders and heterogeneous echogenicity was observed in the right thyroid lobe, classified according to the ACR-TIRADS classification as highly suspicious, with multiple pathological-looking lymphadenopathies. FNA was performed and the result was suspicious for medullary carcinoma (Bethesda V), CBC showed calcitonin: 8202<span class="elsevierStyleHsp" style=""></span>pg/ml (0–10 pg/ml), metanephrines normal, carcinoembryonic antigen: 730.98<span class="elsevierStyleHsp" style=""></span>ng/ml (0–5<span class="elsevierStyleHsp" style=""></span>ng/ml).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Surgical intervention was performed by means of total thyroidectomy and central and lateral lymphadenectomy, with the result in anatomical pathology of medullary thyroid carcinoma with lymph node involvement, positive immunohistochemistry for ACTH.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Genetic study was requested with <span class="elsevierStyleItalic">RET</span> gene mutation: M918T (exon 16).</p><p id="par0045" class="elsevierStylePara elsevierViewall">We reached the diagnosis of medullary thyroid carcinoma with advanced disease at bone level, ectopic Cushing's due to ACTH production in medullary thyroid carcinoma.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Treatment was started with fasting levothyroxine 150 mcg after surgery and subsequently with vandetanib 300<span class="elsevierStyleHsp" style=""></span>mg daily.</p><p id="par0055" class="elsevierStylePara elsevierViewall">After surgery and initiation of vandetanib 300<span class="elsevierStyleHsp" style=""></span>mg, calcitonin decreased to 643<span class="elsevierStyleHsp" style=""></span>ng/mL, ACTH 23.8<span class="elsevierStyleHsp" style=""></span>pg/mL, cortisol 10.7<span class="elsevierStyleHsp" style=""></span>μ g/dL, CLU 94 mcg/day (normalisation of ACTH and cortisol values).</p><p id="par0060" class="elsevierStylePara elsevierViewall">The case report shows a rare cause of Cushing's syndrome: medullary thyroid carcinoma. Barbosa et al. report 0.6% ACTH secretion in the more than 1600 patients with MTC in their study.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">MTC-associated ectopic Cushing's syndrome is linked to a high morbidity as described in our patient; those affected generally have a poor prognosis due to the presence of metastatic disease at the time of diagnosis.</p><p id="par0070" class="elsevierStylePara elsevierViewall">At diagnosis, cervical lymph node metastases are present in approximately half of patients and distant metastases in approximately 10% of patients with MTC. While localised disease has a 10-year disease-specific survival of 96%, this decreases to 44% in cases with distant metastases.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In general, cases of ACTH-dependent Cushing's syndrome are due to pituitary aetiology (Cushing's disease), ectopic cases, which are a minority, are largely due to bronchial carcinoid tumour, lung microcytic tumour or pancreatic NET. MTC cases are rare.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Ectopic Cushing's syndrome in MTCs is associated with severe and debilitating side effects, so treatment should be considered even in the case of persistent extensive disease. Systemic therapy with tyrosine kinase inhibitors offers an additional treatment strategy for the control of metastatic disease and is now considered first-line therapy in the context of unresectable disease or progressive metastatic disease, preferably treatment with vandetanib, reportedly with a very rapid decrease in serum cortisol levels in series of patients. Vandetanib inhibits the tyrosine kinase activity of the RET receptor, vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. All three receptors are involved in the genesis of MTC.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Medical therapy (ketoconazole, metyrapone, mitotane, mifepristone) is generally ineffective and poorly tolerated. Cytoreduction of the tumour is unlikely to be complete, as these patients often have multiple sites of extensive disease. Surgical intervention with bilateral adrenalectomy is another option available for some patients.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0090" class="elsevierStylePara elsevierViewall">Viyey Kishore Doulatram Gamgaram is the beneficiary of a "Rio Hortega" research contract (CM21/00214, Instituto de Salud Carlos III).</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.B. 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Triggiani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2174/1871530319666181220165350" "Revista" => array:6 [ "tituloSerie" => "Endocr Metab Immune Disord Drug Targets" "fecha" => "2019" "volumen" => "19" "paginaInicial" => "226" "paginaFinal" => "229" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30574858" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000016100000002/v1_202307241700/S2387020623002681/v1_202307241700/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000016100000002/v1_202307241700/S2387020623002681/v1_202307241700/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623002681?idApp=UINPBA00004N" ]
