Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Hepatobiliary neuroendocrine carcinoma: a case report

  • Suzana Manxhuka-Kerliu1Email author,
  • Gordana Petrusevska2,
  • Halit Maloku3,
  • Vjollca Sahatciu-Meka4,
  • Sadushe Loxha5,
  • Naim Loxha6 and
  • Labinot Shahini7
Journal of Medical Case Reports20104:53

https://doi.org/10.1186/1752-1947-4-53

Received: 4 November 2009

Accepted: 18 February 2010

Published: 18 February 2010

Abstract

Introduction

Neuroendocrine carcinoma of the gallbladder is a rather uncommon disease. We report a case of a neuroendocrine tumor that was located in the wall of the gallbladder and that extended into the liver.

Case presentation

A 52-year-old Caucasian woman presented with right-sided abdominal pain, ascites and jaundice. An MRI scan revealed a tumor mass located in the gallbladder wall and involving the liver. A partial hepatectomy and cholecystectomy were performed. Histology revealed a neuroendocrine tumor, which showed scattered Grimelius positive cells and immuno-expressed epithelial and endocrine markers. Our patient is undergoing chemotherapy treatment.

Conclusion

Gastroenteropancreatic neuroendocrine tumors need a multidisciplinary approach, involving immunohistochemistry and molecular-genetic techniques.

Introduction

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) constitute a heterogeneous group of neoplasms. Two major GEP-NET subcategories are intestinal endocrine tumors or carcinoids and pancreatic neuroendocrine tumors (PNETs).

Requests for standardization in the management of patients with gastroenteropancreatic NETs recently resulted in the development of several guidelines, including those proposed by ENETS. The TNM staging system and the grading system are based on the current WHO classifications of endocrine and digestive tumors [14].

The classification of GEP-NETs is based on cell mophology and the mitotic index, with well-differentiated tumors displaying monomorphic appearances and rare mitoses (<2/10 HPF), moderately-differentiated tumors displaying an intermediate morphology and mitotic rate (2-10/10 HPF) and poorly differentiated tumors consisting of pleomorphic cells with a high mitotic index (>10/10 HPF). These three histology categories of GEP-NETs (well, moderately and poorly differentiated) strongly correlates with our patient's survival. Other features of neuroendocrine tumors (such as secretion of hormones and expression of somatostatin receptors) also correlate with histological classification. "Moderately-differentiated" neuroendocrine tumors should be recognized as a subset of GET-NETs with a prognosis that is distinct from well- and poorly-differentiated tumors [5].

Most endocrine tumors are well differentiated and slow-growing. A few are poorly differentiated small-cell endocrine tumors that are rapidly growing and have a poor prognosis [6].

Even though the growth of GEP-NETs is slow in comparison with adenocarcinomas, it is generally recognized that, with the exception of 90% of insulinomas, almost all of them have long-term malignant potential. Most are malignant at the time of diagnosis, with 60% or more presenting with metastasis to the liver. The most common cause of the death is hepatic failure and malignant proliferation.

An active approach to treatment may improve our patient's quality and length of life [7].

Management strategies include surgery for cure or palliation, and a variety of other cytoreductive techniques and medical treatment, including chemotherapy and biotherapy to control symptoms due to hormone release and tumor growth, with somatostatin analogues (SSAs) and alpha-interferon. New biological agents and somatostatin-tagged radionuclides are under investigation [8].

Gallbladder neuroendocrine tumors can cause recurrent upper quadrant pain, while extrahepatic bile duct carcinoids typically produce the sudden onset of biliary colic and painless jaundice and ascites [9]. The histopathology of these tumors may reveal: carcinoids (well-differentiated endocrine tumors); small cell carcinomas (poorly differentiated endocrine carcinomas); and mixed endocrine-exocrine carcinomas [10]. Carcinoid tumors larger than 2 cm often extend into the liver and metastasize. The prognosis of small-cell carcinomas of the gallbladder is poor [11].

Case presentation

A 52 year-old Caucasian woman presented with right-sided abdominal pain (upper quadrant pain), ascites and jaundice. She had been experiencing the abdominal pain for one year.

An MRI revealed a tumor mass located in the liver, extrahepatic bile ducts and gallbladder. Tests done at the time of admission revealed raised levels of serum amylase (490-600 IU/L), abnormal liver function (Gamma-glutamyl transpeptidase 372 IU/L; Alkaline phosphatase 1309 IU/L) and a total bilirubin of 1.90 mg/dl. With a clinical diagnosis of obstructive jaundice, our patient underwent imaging studies. The primary clinical diagnosis was liver tumor. A partial hepatectomy and cholecystectomy were performed.

Part of the liver measured 16 × 13 × 8 cm and the gallbladder 9.5 × 3.5 cm. The tumor was located in the wall of the gallbladder infiltrating the liver. The nodular mass measured 6 cm at its greatest axis, was found in the wall of the gallbladder involving the liver, and was a grey-white to yellow color. Thirteen lymph nodes diameters of 0.3 cm to 1 cm were found.

Specimens were fixed in 10% neutral buffered formalin, and paraffin embedded sections were prepared. The sections were processed for conventional histopathological examination as well as for immunohistochemistry using a standard avidin-biotin-peroxidase complex technique. Negative and positive controls were included for each batch of slides tested.

The tumor was composed of round to fusiform cells with round to ovoid hyperchromatic nuclei, arranged in sheets, nests, cords, and festoons. There were rosette-like structures and tubules present, extensive necrosis, as well as basophilic staining of the vessels. Mitotic figures were frequent.

Carcinoma cells were Grimelius positive. In addition, tumor cells immunoexpressed epithelial markers such as CK, CK7, CK19 +/-, and endocrine markers such as NSE (1+), chromogranin A (1+); while C-KIT was negative, ER negative, PR negative, Alfa fetoprotein negative, CEA negative, Ki67 positive (low <5%), Vimentin negative and synaptophysin negative.

The histopathological diagnosis was a GEP-NET tumor. Our patient is undergoing targeted therapy, including: Gleevec (Novartis) (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8).
Figure 1

Gross examination of the liver and gallbladder.

Figure 2

Tumor cells invading the wall of the gallbladder Hematoxylin and eosin 5×.

Figure 3

Paraffin embedded tissue, histological examination (hematoxylin and eosin 5×).

Figure 4

Paraffin embedded tissue, histological examination (hematoxylin and eosin 20×).

Figure 5

Paraffin embedded tissue, Immunohistochemical examination, Cg A (10×).

Figure 6

Paraffin embedded tissue, Immunohistochemical examination, NSE (20×).

Figure 7

Immunohistochemical examination, CK (20×).

Figure 8

Immunohistochemical examination, CK 19 (20×).

Discussion

Hepatic neuroendocrine carcinoma is extremely rare and was first described in 1958 [12]. As of 2001, only 53 cases have been reported in English literature [9]. These tumors were mostly found in middle-age patients and were more frequently in women.

Neuroendocrine carcinoma of the gallbladder is uncommon in humans. Only 4% of epithelial tumors of the gallbladder are neuroendocrine carcinoma, which is reported to have a poor prognosis [13, 14].

Bile duct and gallbladder neuroendocrine carcinomas arise from pre-existing neuroendocrine cells in the epithelium. Molecular genetic techniques will probably aid in a more clear-cut picture of the molecular background of oncogenesis and the progression of these tumors [15].

GEP-NET tumors should be treated with a multidisciplinary approach, including a partial hepatectomy, prophylactic cholecystectomy, and an excision of the lymph nodes and the primary tumor [1619].

Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors and for whom alternative treatments are limited [20].

Since 2000, patients with somatostatin receptor-positive metastatic, inoperable GEP-NETs and malignant pheochromocytomas have been treated with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3] octreotate (177Lu-octreotate). Results177 of Lu-octreotate treatment in these patients are promising, with a tumor size reduction in 47% of the treated patients [21].

Conclusion

Gastroenteropancreatic neuroendocrine tumors need a multidisciplinary approach, involving immunohistochemistry and molecular-genetic techniques.

Consent

Written informed consent was obtained from our patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Abbreviations

CgA: 

chromogranin

CK: 

cytokeratin

ENETS: 

European Neuroendocrine Tumor Society

GEP-NETs: 

gastroenteropancreatic neuroendocrine tumors

NSE: 

neuron specific enolase

PNETs: 

pancreatic neuroendocrine tumors

TMN: 

tumor-node-metastasis

Declarations

Acknowledgements

This study was supported by the Regional Clinical Center in Peja, Institute of Anatomic Pathology, Faculty of Medicine, University of Prishtina as well as the Institute of Pathology Faculty of Medicine, University Ciril & Metodius, Skopje, R. of Macedonia.

Authors’ Affiliations

(1)
Faculty of Medicine, Institute of Pathology, University of Prishtina
(2)
Faculty of Medicine, Institute of Pathology, St Ciril & Methodius University
(3)
Surgery Clinic, University Clinical Center of Kosovo
(4)
Faculty of Medicine, University Clinical Center of Kosovo
(5)
Faculty of Medicine, Institute of Pathology, University Clinical Center of Kosovo
(6)
Surgery Clinic, Regional Hospital of Peja
(7)
Faculty of Medicine, Institute of Pathology, University Clinical Center of Kosovo

References

  1. Rindi G, Bordi C: Endocrine tumours of the gastrointestinal tract: aetiology, molecular pathogenesis and genetics. Clin Gastroenterol. 2005, 19: 519-534.Google Scholar
  2. Oberg K, Astrup L, Eriksson B, Falkmer SE, Falkmer UG, Gustafsen J, Haglund C, Knigge U, Vatn M, Valimaki M: Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I--General overview. Acta Oncol. 2004, 43: 617-625. 10.1080/02841860410018575.View ArticlePubMedGoogle Scholar
  3. Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B: TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006, 449: 395-401. 10.1007/s00428-006-0250-1.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Rindi G, de Herder WW, O'Toole D, Wiedenmann B: Consensus guidelines for the management of patients with digestive neuroendocrine tumors: why such guidelines and how we went about it. Neuroendocrinology. 2006, 84: 155-157. 10.1159/000098006.View ArticlePubMedGoogle Scholar
  5. Strosberg JR, Coppola D, Neumann A, Kvols L: Clinicopathologic analysis of well, moderately and poorly differentiated gastroenteropancreatic neuroendocrine tumors. J Clin Oncol. 2007, 25: 18S-Google Scholar
  6. Hamilton SR, Aaktonen LA: Pathology & Genetics, Tumors of the Digestive System. WHO. 2000, 214-216.Google Scholar
  7. Thompson GB, van Heerden JA, Grant CS, Carney JA, Ilstrup DM: Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery. 1988, 104: 1011-1017.PubMedGoogle Scholar
  8. Massironi S, Sciola V, Peracchi M, Ciafardini C, Pia Spampatti M, Conte D: Neuroendocrine tumors of the gastro-entero-pancreatic system. World J Gastroenterol. 2008, 14 (35): 5377-5384. 10.3748/wjg.14.5377.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Bosl GJ, Yagoda A, Camara LL: Malignant carcinoid of the gallbladder: third reported case and review of the literature. J Surg Oncol. 1980, 13: 215-222. 10.1002/jso.2930130305.View ArticlePubMedGoogle Scholar
  10. Albores-Saavedra J, Henson DE: Tumors of the Gallbladder and Extrahepatic Bile ducts. Radiographics. 2002, 22: 387-413.View ArticleGoogle Scholar
  11. Yamamoto M, Nakajo S, Miyoshi N, Nakai S, Tahara E: Endocrine cell carcinoma (Carcinoid) of the gallbladder. Am J Surg Pathol. 1989, 13: 292-302.View ArticlePubMedGoogle Scholar
  12. Edmondson HA: Tumors of the Liver and Intrahepatic Bile Ducts. Section 7. Fascicle 25. 1958, Washington DC: Armed Forces Institute of Pathology, 193-195.Google Scholar
  13. Iwao M, Nakamura M, Enjoji M, Kubo H, Fukotomi T, Tanabe Y, Nishi H, Taguchi k, Kotoh K, Nawata H: Primary hepatic carcinoid tumor: case report and review of 53 cases. Med Sci Monit. 2001, 7: 746-750.PubMedGoogle Scholar
  14. Albores-Saavedra J, Molberg K, Henson DE: Unusual malignant epithelial tumors of the gallbladder. Semin Diagn Pathol. 1996, 13: 326-338.PubMedGoogle Scholar
  15. Maitra A, Tascilar M, Hruban RH, Offerhaus GJ, Albores-Saavedra J: Small cell carcinoma of the gallbladder. A clinicopathologic, immunohistochemical, and molecular pathology study of 12 cases. Am J Surg Pathol. 2001, 25: 595-601. 10.1097/00000478-200105000-00005.View ArticlePubMedGoogle Scholar
  16. Kazuyoshi N, Masazumi T, Hideak N, Hitoshi I: Composite glandular-endocrine cell carcinoma of the extra-hepatic bile duct: immunohistochemical study. Pathology. 1993, 25: 90-94. 10.3109/00313029309068910.View ArticleGoogle Scholar
  17. Albores-Saavedra J, Klimstra D, Henson DE: Tumor of the Gallbladder, Extrahepatic Bile Ducts, and Ampulla of Vater. 2000, Washington DC: Armed Forces Institute of PathologyGoogle Scholar
  18. Cavazzana AO, Fassima AS, Tollot M, Ninfo V: Small-cell carcinoma of the gallbladder. An immunocytochemical and ultrastructural study. Pathol Res Pract. 1991, 187: 472-476.View ArticlePubMedGoogle Scholar
  19. Fujii H, Aotake T, Horiuchi T, Chiba Y, Imamura Y, Tanaka K: Small cell carcinoma of the gallbladder: a case report and review of 53 cases in the literature. Hepatogastroenterology. 2001, 42: 1588-1593.Google Scholar
  20. de Keizer B, van Aken MO, Feelders RA, de Herder WW, Kam BLR, van Essen M, Krenning EP, Kwekkeboom DJ: Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3] octreotate. Eur J Nucl Med Mol Imaging. 2008, 35 (4): 749-755. 10.1007/s00259-007-0691-z.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, van Eijck CH, Esser JP, Kam BL, Krenning EP: Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3] octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005, 23: 2754-2762. 10.1200/JCO.2005.08.066.View ArticlePubMedGoogle Scholar

Copyright

© Manxhuka-Kerliu et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.