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Scientific letter
Neuroendocrine tumour of the gallbladder
Tumor neuroendocrino de la vesícula biliar
Joana Aylhin López Marcano
Corresponding author
aylhin10@gmail.com

Corresponding author.
, José Manuel Ramia Ángel, Roberto de la Plaza Llamas, Alba Manuel Vázquez, Raquel Latorre Fragua
Unidad de Cirugía Hepatobiliopancreática, Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario de Guadalajara, Guadalajara, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Neuroendocrine tumours &#40;NETs&#41; are a heterogeneous group of neoplasms that originate from neuroendocrine system cells&#44; primarily located in the gastrointestinal tract and the lung&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">NETs of the gall bladder &#40;NET-GB&#41; are very uncommon&#58; they account for only 2&#46;1&#37; of all gall bladder tumours and are often an incidental finding during the histopathological examination of the gall bladder following a cholecystectomy&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present two cases of NET-GB and discuss the symptoms&#44; diagnosis and treatment of these uncommon tumours&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Case 1&#58; 51-year-old woman with a history of biliary colic&#46; The ultrasound showed cholelithiasis&#59; the blood tests showed no abnormal values&#46; A scheduled laparoscopic cholecystectomy was performed and she was discharged after 24&#8239;h with no complications&#46; The histological study showed low-grade 1&#46;6&#8239;&#215;&#8239;0&#46;7&#8239;cm NET&#44; G1&#44; Ki67 1&#37;&#44; with positive chromogranin and cystic node with no signs of malignancy&#46; The CT of the chest and abdomen showed no signs of distant metastases&#46; The chromogranin A figure was &#60;5&#8239;ng&#47;ml&#46; There were no signs of recurrence in the annual follow-up at three years with CT and chromogranin&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Case 2&#58; 50-year-old male with a history of type 2 diabetes mellitus&#44; hepatitis C virus infection and schizophrenia&#44; in whom an ultrasound showed a large 1&#8239;cm polyp in the gall bladder&#59; the blood tests showed no abnormal values&#46; A scheduled laparoscopic cholecystectomy was performed and he was discharged after 24&#8239;h with no complications&#46; The histopathological study showed low grade NET&#44; G1&#44; microcarcinoid&#44; with polyp-like configuration&#44; measuring 3&#46;5&#8239;mm&#44; limited to mucosa&#44; Ki67 1&#46;2&#37;&#44; with positive chromogranin and no involvement of the pericystic lymph node &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The CT of the chest and abdomen showed no signs of distant spread&#46; The chromogranin A figure was 130&#8239;ng&#47;ml&#46; There were no signs of recurrence in the annual follow-up at two years with CT and chromogranin&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">NET-GB account for 0&#46;5&#37; of all NETs and are more common in women &#40;68&#37;&#41;&#46; The age of onset varies from 26 to 79 years&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">There are two theories regarding the origin of NET-GB&#46; One postulates that they could originate from multipotent stem cells&#44; ectopic pancreatic tissue or nerve fibres located in the wall of the gallbladder&#44; while the other proposes that they originate from neuroendocrine cells &#40;enterochromaffin or Kulchitsky cells&#41; in the intestinal or gastric metaplasia of the gallbladder epithelium&#44; produced after chronic inflammation caused by cholelithiasis&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Non-functioning NETs are indolent&#44; generally give rise to symptoms derived from the mass effect such as abdominal pain and jaundice&#46; They tend to be diagnosed in advanced stages&#44; with metastasis in approximately 40&#37; of all cases&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Functioning NETs can cause a wide range of signs and symptoms due to hormonal hyperactivity&#46; Carcinoid syndrome&#44; characterised by flushing&#44; hypotension&#44; diarrhoea&#44; wheezing and heart disease caused by serotonin&#44; has been reported in less than 1&#37; of cases of NET-GB&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">NET-GB is rarely diagnosed pre-operatively&#46; By extrapolation of NETs of the digestive tract and pancreas&#44; for NETs the cancer staging manual &#40;version 3&#46;2018&#41; of the American Joint Committee on Cancer recommends CT or MRI and&#44; as appropriate&#44; images based on somatostatin receptors &#40;preferably PET or scintigraphy&#41;&#44; CT of the chest and serum chromogranin or 5-HIAA in urine&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In NET-GB&#44; however&#44; the diagnosis is usually incidental from the histopathological study and the immunohistochemical staining of a surgical specimen taken from a cholecystectomy scheduled due to cholelithiasis or cholecystitis&#44; and only studied by abdominal ultrasound&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> These two cases were only identified in the histopathological study after cholecystectomies indicated for cholelithiasis&#46; The histological diagnosis should include morphology &#40;large versus small cells and differentiation&#41;&#44; staining for chromogranin A and synaptophysin&#44; Ki-67 and mitotic count&#46; This facilitates their classification as&#58; low grade&#44; differentiated &#40;G1&#44; Ki-67 index &#60;3&#37;&#41;&#59; intermediate grade&#44; moderately differentiated &#40;G2&#44; Ki-67 index &#8805;3&#37; and &#8804;20&#37;&#41;&#59; poorly differentiated high grade neoplasms &#40;G3&#44; Ki-67 index &#62;20&#37;&#41;&#44; small or large cell&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The most commonly used serum marker is chromogranin A&#44; secreted by neuronal and neuroendocrine cells&#46; It can be elevated in patients with kidney or liver failure and in patients treated with proton pump inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Chromogranin B&#44; neuron-specific enolase and quantification of 5-HIAA in urine can also be useful&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> They should only be used to support the diagnosis and as indicators of tumour burden and response to treatment&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Resection is the primary treatment approach&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Cholecystectomy is usually sufficient if the cystic node is negative and there is a free margin&#59; otherwise&#44; the surgery should be extended<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and more intensive treatment considered&#44; based on regional lymphadenectomy or IVb-V bisegmentectomy&#46; Adjuvant therapy is recommended in patients with a Ki-67 value of &#62;20&#8211;55&#37;&#44; which is more effective for the small cell subtype&#46; Specific prognostic factors have not been identified in NET-GB&#44; but the proliferative index&#44; differentiation and tumour size are global prognostic factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">According to the NCCN Guidelines&#44; serum chromogranin or 5-HIAA in urine should be analysed and a CT or MRI should be performed between three and 12 months post-resection and every 12&#8211;24 months&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The five-year survival rates for advanced disease are currently 77&#8211;95&#37; when treated with primary tumour resection and adjuvant therapy&#46; However&#44; more aggressive subtypes have been reported&#44; with a fast clinical course in which survival and prognosis are considerably worse&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In conclusion&#44; NET-GB are uncommon and generally non-functioning&#46; They tend to be diagnosed in the histopathological study of the gallbladder after cholecystectomy due to cholelithiasis&#46; The cystic node should be studied to decide whether to use the lymphadenectomy or IVb-V bisegmentectomy approach and adjuvant therapy should be considered based on the proliferative index&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; L&#243;pez Marcano JA&#44; Ramia &#193;ngel JM&#44; de la Plaza Llamas R&#44; Manuel V&#225;zquez A&#44; Latorre Fragua R&#46; Tumor neuroendocrino de la ves&#237;cula biliar&#46; Gastroenterol Hepatol&#46; 2020&#59;43&#58;87&#8211;88&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A&#41; The tumour grows beneath the surface epithelium&#44; forming small nests and trabeculae&#46; The cells are of uniform size&#44; with slightly eosinophilic cytoplasm and an ovoid nucleus&#44; with no significant atypia &#40;H&#38;E&#41;&#46; B&#41; Immunohistochemical staining for chromogranin&#58; intense cytoplasmic positivity is seen in the neoplastic cells&#46;</p>"
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