Acta MedPort2017May;30(5):421-425 Recebido: 04dejunho de2016- Aceite: 14 de novembro2016|  4. OxfordCentreforDiabetes, andMetabolism.ChurchillHospital.Oxford.UnitedKingdom. 3. DepartmentofCardiology. MiltonKeynesHospital.Buckinghamshire.UnitedKingdom. 2. DepartmentofPathology. JohnRadcliffe Hospital. Oxford.UnitedKingdom. 1. ServiçodeEndocrinologia.InstitutoPortuguês deOncologiaLisboaFranciscoGentil.Lisboa.Portugal. RESUMO Joana SIMÕES-PEREIRA 6. 5. 4. 3. 2. 1. REFERÊNCIAS ABSTRACT Metastático Manifestações deTumor NeuroendócrinodoOvárioNão Síndrome CarcinoideeDoençaCardíacacomo Neuroendocrine Tumour Manifestations ofNon-MetastaticOvarian SyndromeandHeartDiseaseas Autor correspondente:JoanaSimõ[email protected] Palavras-chave: uma marcadamelhoriaclínicaetempermanecidolivrededoença eassintomática. e doença carcinoide cardíaca muito sintomática que foi submetida a resseção tumoral seguida de valvuloplastia. A doente demonstrou dem melhorar a evolução clínica destes doentes. Os autores apresentam o caso de uma mulher com tumor neuroendócrino do ovário po avançada cardíaca insuficiência da estabelecimento ao prévia valvular substituição a e entidade desta precoce reconhecimento o Portanto, doentes. destes sobrevivência da adicional diminuição uma acarretam cardíacas alterações Estas única. clínica entidade uma ovário do neuroendócrinos tumores os tornando hepática, metastização de ausência na cardíaca carcinoide doença e cinoide car síndrome apresentar podem ovário do neuroendócrinos tumores os gastrointestinais, neuroendócrinos tumores dos contrário Ao valvular. doença desta desenvolvimento no preponderante papel um provavelmente exercer parece é serotonina a etiologia aparentemente, mas, sua multifatorial A direitas. válvulas das morfo-funcionais alterações por tipicamente caracteriza-se cardíaca pa Esta tologia cardíaca. carcinoide doença a casos, dos metade de cerca em associada, encontra-se mas rara é carcinoide síndrome A Keywords: and hasremainedfreeoftumoursymptomatology. heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement improve the clinical outcome. We report the case of a woman with an ovarian may neuroendocrine established tumour is and highly failure symptomatic heart carcinoid advanced before replacement valve surgical and recognition Early survival. in reduction significant a represents patients these in impairment entity.cardiac clinical of unique burden a additional are The tumours neuroendocrine ovarian such metastases; of absence the in disease heart carcinoid and syndrome carcinoid with present can tumours neuroendocrine appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease syndrome patient.DermatolSurg.2012;38:1863–6. carcinoma cell basal nevoid a in vismodegib of cessation after rebound Asian JOralMaxillofacSurg.2011;23:105–12. expressions. gene their and jaw in tumor odontogenic keratocystic and Clinical syndrome: carcinoma cell basal features and implications of development of basal cell carcinoma in skin Nevoid al. et M, Shikimori aspects. MedOralPatolCirBucal.2008;13:338–43. clinicopathologic syndrome: Sagredo Gorlin-Goltz JM. A, Urizar Aguirre Surg OralMedPatholRadiol.2015;120:396–407. Oral Europeans. North and Asians East affecting syndrome carcinoma características das revisão Port. 2010;23:1119–26. Gorlin-Goltz: de casos. dois com ilustradas maxilofaciais e neurorradiológicas Med Acta Síndrome P. Moniz on update an syndrome: genetics andtreatment.BrJDermatol.2016;174:68–76. naevus cell Basal RA. Schwartz AM, John Wolfe CM, Green WH, Cognetta AB, Hatfield HK. Basal cell carcinoma cell Basal HK. Hatfield Cognetta AB, WH, Green CM, Wolfe S, Sumitomo N, Kanamura K, Yamamoto H, Ichioka T, Yamamoto de García Ortega Amezaga García A, S, Nuño Zepeda O, Arregui Acha MacDonald DS. A systematic review of the literature of nevoid basal cell M, Almeida S, Domingues I, Lima M, Arantes MM, Safronova Simões-Pereira J,etal.Carcinoidheartdiseaseandovarianneuroendocrinetumour Carcinoma,Neuroendocrine;CarcinoidHeartDisease; Tumor; OvarianNeoplasms CarcinomaNeuroendócrino;Doença CarcinoideCardíaca;NeoplasiasdoOvário; ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R  1 , LaiMunWANG ▪

https://doi.org/10.20344/amp.7713 Copyright ©Ordemdos Médicos2017 2 , Attila KARDOS 421 12. 11. 10. 9. 8. 7. 3 , Ashley GROSSMAN acr n poogn. htdrao Poomuo Photomed. Photoimmunol Photodermatol 2014;30:55–61. photoaging. and cancer Rev. Syst database 2016;7:CD011161. Cochrane basal cancers. preventing skin for cell protection squamous and Sun cell al. et J, Gonzalez C, Restrepo Contemp ClinDent.2015;6:106. review. literature and report case a enucleation: and marsupialization by treated tumor odontogenic keratocyst a of follow-up years Five al. et syndrome): updateandliteraturereview. PediatrInt.2014;56:667–74. carcinoma syndrome. Am JMedGenet.1997;69:299–308. cell basal nevoid with persons 105 in manifestations Clinical al. et JJ, Maxillofac Surg. 2015;5:14. Ann syndrome. Gorlin in tumors odontogenic as keratocystic well as carcinomas cell basal of treatment and inhibition signaling Iannacone MR, Hughes MC, Green AC. Effects of sunscreen on skin on sunscreen of Effects AC. Green MC, Hughes MR, Iannacone Rodriguez-Hernandez Solorzano- J, RD, Nova Medina G, AE, Sánchez J, Cirelli R, Silva V,da Mascarenhas L, Pires M, Verzola R, Molon de carcinoma cell basal (nevoid syndrome Gorlin T. Miyashita K, Fujii DiGiovanna R, Kase YangML, B, Pastakia Goldstein AM, VE, Kimonis hedgehog- Vismodegib R. Sader M, Harth P, Booms S, Ghanaati , Acta MedPort2017May;30(5):421-425

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6 7 and 1% - 2% of 4 12 Primary ONET may be subdivided into subdivided be may ONET Primary 5 Acta Med Port 2017 May;30(5):421-425 Port 2017 Acta Med , 40) – Ovarian neuroendocrine tumours (ONET) are rare, NETs secrete vasoactive hormones, including 5-HT, She was submitted to blood and urine tests, cervico- The results were compatible with a CS in association DISCUSSION accounting for 0.3% - 1.0% of all NETs neoplasms. ovarian strumal. and mucinous, trabecular, insular, categories: four the on depends CS ONET-related of incidence reported The type insular the 39%, to 7.8% from ranging type, histological this syndrome. being the most frequently associated to tachykinins, kallikrein and prostaglandins. these Generally, are inactivated in the hepatic parenchyma by monoamine area. Abdominal examination revealed an enlarged with an edge, liver and a palpable mass in the suprapubic area. in both legs. oedema was present Bilateral pitting abdominal-pelvic magnetic resonance imaging (MRI) scan 1). (Table and echocardiogram with elevated 24-hour urinary 5-hydroxyindoleacetic-acid as classified was She CHD. severe and secretion, (5-HIAA) The Association. Heart York New the to according 2-3 stage analogue was initiated (50 μg TDS decrease marked A TDS). μg 100 to titration progressive with in diarrhoea and was observed, but the symptoms tumour to submitted then was She remained. CHD to related resection. The histology confirmed NET tumour, grade 1, in association with a teratoma (Fig.s 1 - 4). Post-operative and 1) (Table 5HIAA urinary B, and A chromogranins serum octreoscan were The negative. definitive resolution of CHD was achieved with bioprosthetic valve replacement of both tricuspid and pulmonary valves. She remains free of any CS the of symptoms recurrenceor tumour cardiac disease, 3 years post-operatively. mmol/24h (10 422 Only abnormal results are shown * Carcinoid 1 The 3-year 2 The detailed cardiological features have been previously published. No definite hepatic metastases are present. Hepatic veins and inferior vena cava appear distended. Small volume within free the abdomen fluidand pelvis. isEarly intrahepatic present biliary dilatation; dilatation of the common Marked wall. pelvic and abdominal the throughout oedema subcutaneous Extensive duct. bile thickness cortical of preservation with dilation, ureteric with hydronephrosis bilateral of degree of both kidneys. Large heterogeneous pelvic mass that appears inseparable from the uterus measuring 12 x cm. No nodal enlargement within the abdomen. 10 x 11 Small bibasal lamellar pleural effusions. regurgitation with mild to moderate pulmonary valve stenosis and regurgitation. Tricuspid Results (0 – 60) 2642 pmol/L A Serum chromogranin (0 – 150) Serum chromogranin B 313 pmol/L 1700 24-hour urine 5-HIAA segments. all involving liver the of lobes both within pattern enhancement peripheral Abnormal R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m Many of the manifestations of the CS the of manifestations the of Many 3 Simões-Pereira J, et al. Carcinoid heart disease and ovarian neuroendocrine tumour neuroendocrine and ovarian heart disease al. Carcinoid J, et Simões-Pereira – Diagnostic exams performed for the assessment of carcinoid syndrome – Diagnostic exams performed for the assessment Neuroendocrine Neuroendocrine tumours (NETs) of the mid-gut, often A A 54-year-old woman, submitted to bariatric Echocardiogram Cervico-thoraco-abdominal MRI Diagnostic exams Blood and urine tests (only abnormal results are shown) (5-HIAA): 5-hydroxyindoleacetic-acid; NR: Normal range; NA: Not available; auscultation evidenced a systolic murmur in the tricuspid 1 Table initially attributed to Physical her previous bariatric surgery. examination did not evidence any cutaneous cyanosis; lesions chest or examination was normal and cardiac She also complained of lower abdominal pain, diarrhoea and flushing, mainly after eating, breath. and The gastrointestinal mild shortness symptoms of and flushing were (Roux-en-Y (Roux-en-Y bypass) and five years ago, cholecystectomy in another institution, more was referred due to bilateral than leg oedema, unresponsive a to 10 cm furosemide, pelvic mass and found on an abdominal ultrasound. CASE REPORT symptomatic cardiac valvular disease in hepatic the metastases due to absence the direct venous of drainage into the ovarian vein and systemic circulation. multiple liver metastases or, rarely, with extensive peritoneal extensive with rarely, or, metastases liver multiple seeding by-passing hepatic present a inactivation. case of However, an ovarian we carcinoid which presented twice the survival rate. survival the twice are due to the (serotonin), secretion which of is 5HT usually Thus, liver. the to vein portal the by transfer after inactivated the CS is almost always associated with the presence of will evidence 31%, right-sided is disease heart carcinoid valve with patients for involvement. rate mortality approximately have CHD without patients carcinoid whereas – generally called the carcinoid syndrome (CS). heart disease (CHD) may be the the disease initial and manifestation more of than 50% of all patients with CS referred to as ’carcinoid tumours’, are associated in up to 30% - 40% of cases with a flushing, constellation of diarrhoea, symptoms – bronchoconstriction and hypotension INTRODUCTION

CASO CLÍNICO synaptophysin (inset, 200x)immunohistochemistry Figure 3 florid by giant cellreaction(inset,200x)tokeratinmaterial( lined is that x) (12.5 component teratoma monodermal 1 Figure – – – Carcinoid Carcinoid component exhibiting positive expression with Right ovary (540 g, 11 x 9 x 7 cm) with mature cystic mature with cm) 7 x 9 x 11 g, (540 ovary Right Simões-Pereira J,etal.Carcinoidheartdiseaseandovarianneuroendocrinetumour ica da Ordem dos Médicos www m o c . a s e u g u t r o p a c i d e m a t c a w. w w s o c i d é M s o d m e d r O a d a c fi í t n e i C a t s i v e R * * * ) 423

iodr I ptet wt OE toe omns drain hormones those ONET this with of patients development In the disorder. for required not is metastases Nevertheless, CS. hepatic of precondition the the which in cases some are there to leading circulation, the enter over- systemic hormones is these metastases, capacity to due liver’s whelmed the when However, oxidases. Figure 2 which is associated with decreased cardiac output, in the in output, cardiac decreased with , associated is including which failure, heart right of venous signs and retroperitoneal and duct collaterals. thoracic via liver the by-passes drainage the whom in metastases node lymph portal system, as well as in cases the of by-passing ovary), extensive (left vein retroperitoneal renal or ovary) (right cava vena internal the via circulation systemic the into directly chromogranin (inset, 200x)immunohistochemistry Figure 4 – – – Carcinoid Carcinoid component exhibiting positive expression with Carcinoid component(12.5x)ofthetumour 8,9 ains ih NT a peet symptoms present can ONET with Patients , Acta MedPort2017May;30(5):421-425

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17 Nevertheless, this usually diagnosed NET in the pre- and co-secretion of 16 19 20 19,20 Updated population-based review of review population-based Updated observed observed a higher incidence believe that gastric NETs are 14 18 et al et and duodenal This association may be coincidental, coincidental, be may association This et al et 15 19 Acta Med Port 2017 May;30(5):421-425 Port 2017 Acta Med , Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis, CY. Ko JB, O’Connell MA, Maggard Diaz-Montes TP, Rosenthal LE, Bristow RE, Grumbine FC. Primary No subsidies or grants contributed to this work. The authors declare that the procedures were followed use in protocols the followed having declare authors The The authors have no conflict of interest to declare. and management. Heart. 2004;90:1224–28. Ann Surg. 2004;240:117–22. carcinoid tumors. This work was presented as a poster at the Annual Meeting Annual the at poster a as presented was work This In summary, we present a case of an ovarian NET 3. 4. 5. described. described. Keshishian in of obese small patients intestine (1.5%) NETs compared to general population. Other authors presence have reported of the gastric operative setting. In fact, upper gastrointestinal endoscopy is recommended in the pre-bariatric surgery evaluation, rendering possible the NET diagnosis before the surgical procedure. Al-Harbi FUNDING SOURCES of metastatic disease, bivalvular and and tumour the of who removal operative by has symptoms been cured of her replacement. These complex patients must be managed by an endocrinologists, experienced oncologists, cardiologists, multidisciplinary pathologists and cardiothoracic surgeons. team including OBSERVATIONS of the Portuguese Society of Endocrinology, Diabetes and 2016. Metabolism, 28-30/01/2016, Coimbra, Portugal, PROTECTION OF HUMANS AND ANIMALS according to the regulations established Research by the and Clinical Ethics Association. Medical Declaration of the World Committee and to the Helsinki CONFIDENTIALITY DATA data publication. at their working center regarding patients’ CONFLICT OF INTEREST probably related to abnormal feeding behavior of the obese the of behavior feeding abnormal to related probably patients. On the other hand, pancreatic NETs have been reported following bariatric surgery, authors These investigation. episodes’ hypoglycemic during described insulin producing tumours glucagon. and GLP-1 but the metabolic alterations, induced by weight loss and may gastrointestinal tract, the of rearrangement anatomical hyperplasia cell islet like alterations, neuroendocrine in result and expansion of the association cannot b-cell be suspected in mass. the particular case of our patient who developed an ovarian NET. presenting with a valvular CS dysfunction and in severe whom right-sided there cardiac was no evidence

424 10

10 reported an 10 CHD is typically right- et al 3 Loop diuretics combined diuretics Loop 12 Persistent overstimulation

11 R e v i s ta C i e n tífi c a d a Or d e m d o s M é d i c o s w w w.a c ta m e d i c a p o r tu g u e s a .c o m increases the synthesis and up- The choice between a mechanical or mechanical a between choice The 3 is not an absolute contraindication to Simões-Pereira J, et al. Carcinoid heart disease and ovarian neuroendocrine tumour neuroendocrine and ovarian heart disease al. Carcinoid J, et Simões-Pereira per se The perioperative management should involve 3 However, somatostatin analogues cannot reverse 10 Kvols LK. Metastatic carcinoid tumors and HC, the Pitot JA, Callahan JB, Seward BK, malignant Khandheria AJ, carcinoid Tajik PA, Pellikka syndrome. Ann NY Acad Sci. 1994;733:464–70. Acad Sci. Ann NY syndrome. et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation. 1993;87:1188–96. This patient presented a past history of Roux-en-Y Treatment Treatment with somatostatin analogues and/or tumour Recently, Recently, Grozinsky-Glasberg Carcinoid heart disease has been reported in up to 60% 1. 2. REFERENCES surgery and the development of certain tumours. neuroendocrine To our knowledge, obesity or the bariatric association surgery between and ONET has not been bypass due to obesity. Interestingly, some authors been reporting the relationship between obesity or have bariatric the use of intravenous infusion the risk of of intraoperative hypotension octreotide and carcinoid to crisis. the in reduce useful be also may corticosteroids and bronchospasm. and flushing control to setting perioperative recurrent symptoms have disease been observed. surgery. Metastatic selected cases, balloon valvoplasty of the right-sided valves valves right-sided the of valvoplasty balloon cases, selected was associated with symptomatic improvement in patients with stenotic tricuspid or pulmonary valves, although The definitive therapy of CHD replacement. valvular can only be provided by bioprosthetic valve should be an individualised decision. In with fluid and salt restriction and compressionmay initially stockings relieve the symptoms if the CHD is mild, but may decrease the cardiac output in advanced cases. debulking/resection may improve the CS as negative well haemodynamic as impact the of tumour hormones CHD. on dysfunction. valvular established valve the plaques involve mainly the subvalvular apparatus leading to regurgitation. pulmonary valve causes adhesion of pulmonic leaflets to of mixture a in resulting endocardium arterial pulmonary the tricuspid the in whereas regurgitation, and stenosis valvular apparatus. CHD is strongly suggested on echocardiograms on suggested strongly is CHD apparatus. by the concomitant dysfunction of pulmonary and tricuspid valves. The deposition of plaques on the leaflets of in the cardiac heart valves. of these receptors regulation of transforming This cytokine growth leads to the factor-β1 deposition of plaques (TGF-β1). in valve This clinical entity is probably multifactorial and mediated to appears Serotonin hormones. vasoactive different the by receptors through CHD of development the in role key a play situated in the lungs or there is a patent foramen ovale. is a patent foramen the lungs or there situated in extensive review on CHD highlighting its pathophysiology. of patients with carcinoid syndrome. sided, as the left side is usually spared due to inactivation of vasoactive hormones in the lungs, unless the tumour is absence of metastases. absence

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