The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffin
cells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge of
these gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cell
neuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, who
already underwent quadrantectomy and sentinel lymph-node biopsy for breast cancer. The patient underwent radiotherapy for
breast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free from
disease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases,
specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladder
with another malignancy has been reported only once.The contemporary presence of the two neoplasms could reflect that bioactive
agents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation

Aiello, P

ARAGONA, Francesco

Buscemi, Salvatore

CARUSO, Anna Maria

DI VITA, Gaetano Giuseppe

PATTI, Rosalia

TERRITO, Valentina

Case Reports in Surgery

PubMed

The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffin cells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge of these gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cell neuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, who already underwent quadrantectomy and sentinel lymph-node biopsy for breast cancer. The patient underwent radiotherapy for breast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free from disease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases, specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladder with another malignancy has been reported only once. The contemporary presence of the two neoplasms could reflect that bioactive agents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation

Paolo Aiello

Francesco Aragona

Valentina Territo

Anna Maria Caruso

Rosalia Patti

Salvatore Buscemi

Gaetano Di Vita

Directory of Open Access Journals

Concomitant Small Cell Neuroendocrine Carcinoma of Gallbladder and Breast Cancer

The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffin cells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge of these gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cell neuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, who already underwent quadrantectomy and sentinel lymph-node biopsy for breast cancer. The patient underwent radiotherapy for breast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free from disease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases, specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladder with another malignancy has been reported only once. The contemporary presence of the two neoplasms could reflect that bioactive agents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation.</jats:p

Crossref

Archivio istituzionale della ricerca - Università di Palermo

Case ReportConcomitant Small Cell Neuroendocrine Carcinoma ofGallbladder and Breast CancerPaolo Aiello,1 Francesco Aragona,2 Valentina Territo,1 Anna Maria Caruso,1Rosalia Patti,1 Salvatore Buscemi,1 and Gaetano Di Vita11 Dipartimento di Discipline Chirurgiche, Oncologiche e Stomatologiche, Unita` di Chirurgia Generale,Universita` degli Studi di Palermo, Via Liborio Giuffre` No. 5, 90127 Palermo, Italy2 Dipartimento di Patologia Umana, Facolta` di Medicina e Chirurgia, Policlinico Universitario, 90127 Palermo, ItalyCorrespondence should be addressed to Gaetano Di Vita; divitagaetano@libero.itReceived 3 June 2014; Revised 9 September 2014; Accepted 20 September 2014; Published 25 September 2014Academic Editor: Dimitrios MantasCopyright © 2014 Paolo Aiello et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffincells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge ofthese gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cellneuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, whoalready underwent quadrantectomy and sentinel lymph-node biopsy for breast cancer. The patient underwent radiotherapy forbreast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free fromdisease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases,specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladderwith anothermalignancy has been reported only once.The contemporary presence of the two neoplasms could reflect that bioactiveagents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation.1. IntroductionNeuroendocrine tumors (NETs) are rare neoplasms, arisingfrom enterochromaffin cells, usually disposed in the mucosaof gastric and respiratory tracts. Neuroendocrine cells havesome biochemical and morphological characteristics: thesecells contain dense core secretory granules and lack axonsand synapses and are able to produce neurotransmitters,neuromodulators, or neuropeptide hormones. Incidence ofNETs is 5.25 cases per 100,000 person-years in the UnitedStates [1]. NETs most frequently arise in the gastrointestinaltract and in the respiratory tract secondarily but can occur inany location. According to the data collected by the Surveil-lance, Epidemiology, and End Results (SEER) program ofNational Cancer Institute of the USA in the period of 1973–2005 using SEER 17 Registry, of 16005 of NETs of the entiregastrointestinal system only in 229 cases (1.4%)was the originof the gallbladder [2].The NETs comprise a heterogeneous group of neoplasmsthat vary from low-grade malignancy tumors to tumors withhigh malignancy. A recent classification published in 2010by the World Health Organization divides NETs into threecategories [3]: neuroendocrine tumor (NET) which includesclassic carcinoid tumor, neuroendocrine carcinoma (NEC),and mixed adenoneuroendocrine carcinoma (MANEC). ANEC is defined as a high-grade malignant neuroendocrineneoplasm composed of either small or intermediate to largecells with marked nuclear atypia and a high proliferationfraction.NETs have a good prognosis, while NEC and MANEChave a poor prognosis. Incidence of various types of NETsin the entire gastrointestinal system is different; however, theratio of tumor with good prognosis to tumor with severeprognosis in the gallbladder is very low in comparison toother gastrointestinal locations [2]. Because of rarity of NECHindawi Publishing CorporationCase Reports in SurgeryVolume 2014, Article ID 945921, 4 pageshttp://dx.doi.org/10.1155/2014/9459212 Case Reports in Surgeryof gallbladder, knowledge of these tumors is limited andbased on isolated case reports or very small series.We describe a case of incidental small cell NEC ofthe gallbladder (NEC-SC-GB) concomitant with moderatelydifferentiated invasive ductal carcinoma of the breast. To thebest of our knowledge, this is the first case that describes thisassociation.2. Case PresentationA55-year-old female, with symptoms related to cholelithiasis,was admitted to our hospital. She reported a 20-day historyof intermittent right upper quadrant pain radiating to theback, associated with nausea and bloating sensation. Herfamily history included father with lung adenocarcinoma.Her personal history included right ovary salpingectomy forendometriosis cyst, viscerolysis for bowel obstruction causedby adhesions, and repair of a median abdominal incisionalhernia using polypropylene mesh. A quadrantectomy andsentinel lymph-node biopsy for moderately differentiatedinvasive ductal carcinoma of the breast G2pT1cN0, withestrogens receptors of 90%, progesterone receptors of 85%,and HER2/neu = 1+ and Ki-67 < 14%, was performed onemonth before. At the time of admission, she had normalvital parameters and laboratory investigations. At the physicalexamination, tenderness in epigastric region and in the rightupper quadrant was revealed with no evidence of jaundice.The patient showed an abdominal ultrasound and contrast-enhance abdominal computed tomography: lumen of thegallbladder was occupied by numerous stones with a non-thickened wall, no evidence of biliary dilatation was noted,and there was no ascites.The chest X-ray revealed no unusualfindings. After a laparoscopic access, we carried out, for thepresence of numerous adhesions, an open cholecystectomy.There was no evident locoregional lymphadenopathy.The patient had an uneventful postoperative recovery andwas discharged home after two days. On gross inspection,the gallbladder measured 10 cm in length, some stoneswere found in its lumen, and a polypoid, whitish lesion,in correspondence with the bottom, measuring 1,5 cm wasfound in its body. Final histologic examination revealeda neuroendocrine small cell carcinoma of the gallbladder.Tumour was seen infiltrating into the muscular layer butnot through the serosa of the gallbladder. Resected marginswere free from tumor. Two lymph nodes measuring about4mm were isolated from the surgical specimen: the analysisof one lymph node revealed focal metastatic deposits ofneoplastic cells (Figure 1), whereas in the other one nodeposits of tumor cells were found. Immunohistochemicalstudies revealed cells strongly positive for chromogranin(Figure 2) and synaptophysin (Figure 3) and negative forthyroid transcription factor-1.Postoperative imaging studies did not show residualdisease either locally or remotely. Patient was subjected toradiotherapy for breast cancer and six cycles of chemotherapywith cisplatin and etoposide were administered. Eighteenmonths after surgery, the patient was free from disease.Figure 1: Focal metastatic colonization of the pericystic lymphnode.Figure 2: Positivity of the tumor to the immunohistochemicalstaining for chromogranin.3. DiscussionNEC-SC-GB was described by Albores-Saavedra et al. in 1981[4]. Subsequently, only a case report or small series of patientshave been published [5]; however, a paucity of data on thistumor persists; Mahipal and Gupta [6] reported that 74 caseshave been described until 2011.Hystogenesis of NEC-SC-GB is unclear. Some authors [7]believe that it arises from rare neuroendocrine cells normallypresent in the body and fundus of the gallbladder. Otherauthors believe that it originates from foci of intestinal orgastric metaplasia [8], usually associated with long-standingchronic inflammation due to cholelithiasis [9]. The age atpresentation has a range from 38 to 81 years with a higherincidence in the sixth and seventh decade of life; the femaleto male ratio is 2.2 [2].Often stones are associated with the NEC-SC-GB, whilerarely it presents as an isolated lesion wall [10]. Tumor sizeranges from 0.4 cm to over 10 cm. The symptomatology hasno pathognomonic characters but is similar to that of lithiasisin the early stageNEC-SC-GB and in the later stages is similarto that of adenocarcinoma.The secretory activity characteristic of NETs has rarelybeen observed in NEC-SC-GB and in this case, the tumorwas in an advanced stage. Cases with symptoms of ghrelinsecretion [11] of insulin [12], of pancreatic polypeptide [13],Case Reports in Surgery 3Figure 3: Positivity of the tumor to the immunohistochemicalstaining for synaptophysin.of paraneoplastic sensory neuropathy [14], or of hypona-tremia [15] have been described.These tumors are usually diagnosed incidentally atthe histological examination of gallbladder specimens aftercholecystectomy, during autopsy, or during an ultrasoundexamination or computed tomography performed for otherreasons [16]. In cases of multiple cholelithiases we should payparticular attention to imaging investigations because calculican disguise cancer as we observed.Coexistence of malignant tumors of different histologictypes with carcinoids has been a source of significant debate,throughout the past several decades [17]. A synchronous ormetachronous neoplasia with carcinoid develops in approxi-mately 25% of cases [17, 18]. These lesions are located morefrequently in the gastrointestinal tract. An explanation forthe high frequency is not clear. It presumably reflects the factthat some of the bioactive agents secreted by these lesionsare known mitogens for a variety of cell types. Therefore, it isprobable that, over time, the prolonged action of such growthfactors may promote phenotypic changes in susceptible cellsand induce neoplastic transformation. To the best of ourknowledge, only Petersen et al. [19] reported a case of a73-year-old woman with NEC-SC-GB concomitant with anendometrioid adenocarcinoma of the ovary. Therefore, thecase that we observed represents the second case of multipletumors reported in the literature.Simple cholecystectomy is probably an adequate ther-apy for early detected and preinvasive cancer, while, foradvanced neoplasms, a more aggressive radical surgicaltreatment, including radical cholecystectomy and regionallymphadenectomy combined with a hepatic resection inorder to obtain adequate free margins, is needed [9].Role of radiotherapy and chemotherapy remains unde-fined because of the paucity of data of this rare disease.Thereis no standard indication for adjuvant therapy, so decisionson adjuvant therapy are based on clinical situations, such asdissemination state, or on characteristics of the patients suchas old age, the presence of medical comorbidities, or patient’srefusal.Prognosis of this pathology is worse due to the advancednature of the disease at diagnosis [6], tumor size beingoften greater than 4 cm, and also the majority of patientspresenting with liver metastases or lymph nodes or withhepatic infiltration.A clear assessment of prognosis ofNEC-SC-GB is difficultdue to limited knowledge, because cases described have alimited follow-up. Kim et al. [5] and Eltawil et al. [9] reportedin a series of cases of NEC-SC-GB collected by SEER that the5-year relative survival was 0%, despite the fact that at leasttwo patients had tumor size <2 cm [9]. Mahipal and Gupta[6] in the review of literature report a median survival of 9months with a range of 1–189 months.The few reported caseswith tumors of limited size [10, 20] have a limited follow-upand were detected as incidental findings.4. ConclusionNEC-SC-GB is a rare malignancy with poor prognosis.Because of rarity of reported cases specific prognostic factorshave not been identified, but high tumor size, depth ofinvasion, and metastases are probably associated with theprognosis. Our case has not progressed 18 months aftersurgery, suggesting that aggressive multimodal treatmentmay be helpful.We emphasize the need for surgical treatment of any wallthickening or polypoid lesion of the gallbladder in elderlywomen, relying on the pathologist and immunohistochem-istry analyses for the final diagnosis. However, presence ofgallstones can mask the tumor. Finally, although it has beenreported only two cases of multiple tumours, this possibilityshould not be overlooked.ConsentWritten informed consent was obtained from the patient forpublication of this case report and the accompanying images.A copy of the written consent is available for review.Conflict of InterestsThe authors declare that there is no conflict of interestsregarding the publication of this paper.References[1] J. C. Yao, M. Hassan, A. Phan et al., “One hundred yearsafter “carcinoid”: epidemiology of and prognostic factors forneuroendocrine tumors in 35,825 cases in the United States,”Journal of Clinical Oncology, vol. 26, no. 18, pp. 3063–3072, 2008.[2] J. Albores-Saavedra, K. Batich, S. Hossain, D. E. Henson, and A.M. Schwartz, “Carcinoid tumors and small-cell carcinomas ofthe gallbladder and extrahepatic bile ducts: a comparative studybased on 221 cases from the Surveillance, Epidemiology, andEnd Results Program,” Annals of Diagnostic Pathology, vol. 13,no. 6, pp. 378–383, 2009.[3] F. T. Bosman, F. Carneiro, R. H. Hruban, and N. D. Theise,WHO Classification of Tumours of the Digestive System, TheInternational Agency for Research on Cancer, Lyon, France, 4thedition, 2010.[4] J. Albores-Saavedra, H. Cruz-Ortiz, A. Alcantara-Vazques, andD. E. Henson, “Unusual types of gallbladder carcinoma. A4 Case Reports in Surgeryreport of 16 cases,” Archives of Pathology and LaboratoryMedicine, vol. 105, no. 6, pp. 287–293, 1981.[5] J. Kim, W. J. Lee, S. H. Lee et al., “Clinical features of20 patients with curatively resected biliary neuroendocrinetumours,” Digestive and Liver Disease, vol. 43, no. 12, pp. 965–970, 2011.[6] A. Mahipal and S. Gupta, “Small-cell carcinoma of the gall-bladder: report of a case and literature review,” GastrointestinalCancer Research, vol. 4, no. 4, pp. 135–136, 2011.[7] H. Kuwabara and H. Uda, “Small cell carcinoma of the gall-bladder with intestinal metaplastic epithelium,” Pathology Inter-national, vol. 48, no. 4, pp. 303–306, 1998.[8] S. Wakiyama, K. Yoshimura, M. Shimada, K. Kajiyama, and K.Sugimachi, “Heterotopic gastric mucosa in a gallbladder withan anomalous union of the pancreatobiliary duct: a case report,”Hepato-Gastroenterology, vol. 45, no. 23, pp. 1488–1491, 1998.[9] K. M. Eltawil, B. I. Gustafsson, M. Kidd, and I. M. Modlin,“Neuroendocrine tumors of the gallbladder: an evaluationand reassessment of management strategy,” Journal of ClinicalGastroenterology, vol. 44, no. 10, pp. 687–695, 2010.[10] G. Virz`ı, S. Ragazzi, P. D’Agati et al., “Image of the month.Moderately differentiated neuroendocrine carcinoma of thegallbladder,” Archives of Surgery, vol. 143, no. 1, pp. 95–96, 2008.[11] T. Walter, L. Chardon, V. Hervieu et al., “Major hyperghreline-mia in advanced well-differentiated neuroendocrine carcino-mas: report of three cases,” European Journal of Endocrinology,vol. 161, no. 4, pp. 639–645, 2009.[12] J. E. Ahn, J. H. Byun, M. S. Ko, S. H. Park, and M. G.Lee, “Neuroendocrine carcinoma of the gallbladder causinghyperinsulinaemic hypoglycaemia,” Clinical Radiology, vol. 62,no. 4, pp. 391–394, 2007.[13] N. N. Marrano, L. S. Blevins, A. A. Gal, and W. P. McGuire,“Pancreatic polypeptide hypersecretion associated with a neu-roendocrine carcinoma of the gallbladder,” American Journal ofthe Medical Sciences, vol. 317, no. 1, pp. 55–58, 1999.[14] N. O. Uribe-Uribe, A. M. Jimenez-Gardun˜o, D. E. Henson,and J. Albores-Saavedra, “Paraneoplastic sensory neuropathyassociated with small cell carcinoma of the gallbladder,” Annalsof Diagnostic Pathology, vol. 13, no. 2, pp. 124–126, 2009.[15] E. S. Ng, K. Venkateswaran, S. I. Ganpathi, and B. Y. Chuah,“Small cell gallbladder carcinoma complicated by paraneoplas-tic hyponatremia: a case report and literature review,” Journal ofGastrointestinal Cancer, vol. 41, no. 4, pp. 264–268, 2010.[16] V. Anjaneyulu, G. Shankar-Swarnalatha, and S. C.-S. Rao,“Carcinoid tumor of the gall bladder,” Annals of DiagnosticPathology, vol. 11, no. 2, pp. 113–116, 2007.[17] I. M. Modlin, K. D. Lye, and M. Kidd, “A 5-decade analysis of13,715 carcinoid tumors,” Cancer, vol. 97, no. 4, pp. 934–959,2003.[18] J. R. Olney, L. F. Urdaneta, A. S. Al-Jurf, P. R. Jochimsen, and S.S. Shirazi, “Carcinoid tumors of the gastrointestinal tract,” TheAmerican Surgeon, vol. 51, no. 1, pp. 37–41, 1985.[19] M. Petersen, F. Meyer, T. Kalinski, J. Bischoff, U. R. M. Bohr,and H. Lippert, “Rare neuroendocrine carcinoma of the gallbladder: coincidental occurrence of an endometrioid ovarianadenocarcinoma,” Deutsche Medizinische Wochenschrift, vol.134, no. 1-2, pp. 19–22, 2009.[20] P. Nau, J. Liu, M. Dillhoff, M. Forster, J. Hazey, and S. Melvin,“Two cases of small cell carcinoma of the gallbladder,” CaseReports in Medicine, vol. 2010, Article ID 453624, 4 pages, 2010.Submit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Concomitant Small Cell Neuroendocrine Carcinoma of
Gallbladder and Breast Cancer

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Concomitant Small Cell Neuroendocrine Carcinoma of Gallbladder and Breast Cancer

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