Current surgical management of pancreatic endocrine tumor liver metastases

Theodoros E Pavlidis, Kyriakos Psarras, Nikolaos G Symeonidis,Efstathios T Pavlidis and Athanasios K Sakantamis

Thessaloniki, Greece

Current surgical management of pancreatic endocrine tumor liver metastases

Theodoros E Pavlidis, Kyriakos Psarras, Nikolaos G Symeonidis,Efstathios T Pavlidis and Athanasios K Sakantamis

Thessaloniki, Greece

(Hepatobiliary Pancreat Dis Int 2011; 10: 243-247)

pancreatic endocrine tumors;pancreas islet cell neoplasms;neuroendocrine tumors;liver metastases;surgical management;debulking surgery

Introduction

Islet cells represent only 1%-2% of the pancreatic mass,and pancreatic endocrine tumors (PETs) are rare neoplasms. They may cause symptoms of hormonal hyper-secretion, but they may also be non-functioning and asymptomatic. They are slow-growing lesions, less aggressive than exocrine pancreatic adenocarcinoma; they have a variable prognosis, and in general good long-term survival rates.[1-7]They appear either sporadically, which is more common, or together with other neoplasms in cases of multiple endocrine neoplasia (MEN-1) syndrome,[8]where the malignancy and aggressive behavior are less pronounced.[5]The most common functioning PET is insulinoma (75%), with an incidence of 4 cases per 1 million of population per year.[9]The location of the primary tumor can be identi fi ed by the combination of different imaging strategies, such as pre- and intraoperative US, contrast-enhanced CT and MRI.[1,7]

In a recent large multicenter study from Italy, tumors were mostly non-functioning (75.4%), and the diagnosis was incidental in 38.7% of cases. Liver metastases were present in 28.6% of them, predominantly in the nonfunctioning cases, while lymph nodal metastases were found in 28.3%.[10]

The recurrence rate of PETs after curative R0 resection is 24.6%, in most of the cases appearing as liver metastases (75%) after a mean of 7.3±4.5 years after surgery. Risk factors for recurrence are considered the MEN-1 syndrome, a tumor size ≥4 cm, the presence of liver metastases at the time of initial diagnosis, and TNM stages III or IV.[11]Among the prognostic factorsfor survival,[12]successful radical surgery of the primary site is critical.[13,14]

The expression levels of the PAX8 gene in normal islet cells and in primary or metastatic PETs is useful nowadays, because its immunostaining may be helpful to localize an occult primary site, when only the presence of liver metastases is evident. In addition, it can be used as a prognostic marker, since the loss of its expression indicates a more malignant behavior.[15]The expression of the FGF13 gene is another new prognostic marker associated with a worse outcome.[16]Based on KIT and CK19 co-expression, PETs can be classi fi ed as of low, intermediate or high risk regarding their malignant behavior.[17]The expression of other cellular molecules has also been used for the assessment of invasive potential and metastatic spread. Both betacatenin and E-cadherin correlate strongly with lymph node and liver metastases of PETs.[18]

The management of metastatic disease in PETs demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved.[19-21]Although surgery is the cornerstone of management, several new modalities may be used alternatively in advanced cases, such as palliative drugs,chemotherapeutic agents or radiofrequency ablation.The latter has lately been used increasingly for liver metastases. However, despite all these advancements,there is no clear improvement in survival.[2]

Early diagnosis and accurate localization

The early diagnosis and the accurate localization of metastatic sites, most commonly in the liver, are of great importance. Chromogranin A, a serum glycoprotein,is an early diagnostic marker for neuroendocrine tumors and also permits an accurate screening postoperatively since it is produced in signi fi cant quantities in 90%-100% of cases. In addition, it is used as a prognostic marker for the survival of patients with malignant carcinoids of the small intestine.[22-24]

Modern imaging strategies including abdominal echogram, CT and MRI, positron emission tomography,and somatostatin receptor scintigraphy (sensitivity of 90% for receptor-positive tumors), can identify the exact locations of metastatic sites.

Treatment

The treatment goals focus on radical surgical excision,inhibition of tumor cell growth, relief of symptoms of hormonal hyper-secretion, and fi nally in a good quality of life in the long-term.

Surgical options

Surgical options include radical tumor excision,palliative excision aiming to relieve symptoms in cases of medical treatment failure, and treatment of lifethreatening complications such as gastrointestinal hemorrhage, obstructive jaundice or ileus.[5,25-27]These options are often a subject for debate. For metastatic tumors in the liver, the main controversies concern cytoreduction or debulking surgery, transplantation and management of MEN-1 patients.[5]

Radical excision aims to completely remove the primary tumor and the metastases at the same time.Although this excision is an ideal option, it is not feasible in most cases.[28]It is mainly indicated for patients with liver metastases and few or no metastases elsewhere. In these patients the primary tumor can be adequately removed and their condition is good enough to undergo such operation. Radical excision in cases of single hepatic lobe localization (typical partial hepatectomy) has a 5-year survival rate of up to 90%.Total hepatectomy and transplantation in cases of bilobar localization is less commonly performed, and is reserved for patients younger than 55-60 years.[5,29]For malignant non-functioning PETs, the main predictive factor for survival is curative resection of the primary tumor.[30]

Palliative resections include aggressive tumor debulking surgery aiming to remove at least 90% of the tumor, combined with additional tumor destructive techniques, in cases of well-differentiated carcinomas that cannot be radically removed. In neuroendocrine tumors, which are usually neoplasms of slow growth,the typical tumor-excision contra-indications of other carcinomas do not apply (lymph-node or distal metastases, superior mesenteric or portal vein invasions). This level of management provides a 5-year survival in up to 71% of patients (mean survival time 76 months), a disease-free evolution in 5% (with a mean disease-free period of 21 months), and a symptomfree evolution in 24% (with a mean symptom-free period of 26 months).[19]The results are even better in cases of malignant insulinomas, where after radical resections the disease-free survival can be up to 5 years with a recurrence rate of 63%, whereas after palliative resections the mean survival is 4 years, but it is only 11 months if left untreated (tumor biopsy only).[5,25-27]It has been reported that extended survival rates can be achieved in malignant VIPomas or calcitonin-secreting malignant PETs by an aggressive surgical approach combined with other modalities such as radioablation for liver metastases.[31,32]

Laparoscopic experience in the management of PETs is still limited; it gains, however, all the bene fi ts of minimally invasive surgery and it can achieve negative resection margins in a high proportion of patients.[33,34]

Additional techniques in cases of liver metastases

These are, fi rst, hepatic artery embolization or chemoembolization (spongostan, gel-foam) in cases of systemic therapy failure, providing a response rate of 50%-90% with a mean duration of the result for 10-15 months.[25]Chemoembolization makes strong chemotherapeutics (doxorubicin, cisplatin)in high concentrations administered directly to the liver tissues, and it is recommended for symptomrelief in rapidly growing tumors. The combination of chemoembolization with systemic chemotherapy provides even higher rates of response and better survival rates.[24]Hepatic artery embolization or chemoembolization has a satisfactory long-term outcome with a mean survival of 3.5 years.[35]Some promising preliminary results have been reported in cases of PETs with bilobar liver metastases treated by transarterial chemoembolization with doxorubicineluting beads.[36]

Local destruction techniques include ethanol administration, cryotherapy, and radiofrequency ablation,which can be performed either transabdominally,laparoscopically or on laparotomy.[25,37-39]Palliative radiotherapy with radiolabeled somatostatin analogs(peptide receptor radionuclide therapy) is useful in inoperable or metastatic PETs with positive somatostatin receptors. The reported response rates are 28%-38%, and disease progression-free survival is 22-36 months.[40,41]This therapy can be applied either locally with radiolabelled octreotide (111In-DTPA,90Y-DOTA,177Lu-DTPA) or as external radiation in cases of bone metastases.

First-line chemotherapy includes the combination of streptozotocin with 5- fl uorouracil or doxorubicin.Its response rates are limited to between 25% and 30%,with a mean duration of 20-24 months, while symptomrelief can be achieved in 50% of cases. Second-line chemotherapy includes interferon-α and octreotide.Cisplatin and etoposide administration is limited to rapidly-growing tumors.[25,26]

Medical prescription

Medical prescription is indicated for patients with non-resectable metastatic disease, high-risk patients who cannot be operated on, and patients with symptoms after an unsuccessful operation or tumor relapse. Commonly administered drugs include diazoxide for insulinomas(anti-hypertensive with hyperglycemic effect), calcium channel blockers (verapamil), and somatostatin analogs(octreotide) for the relief of symptoms. The latter are only sporadically and temporarily used to treat insulinomas, but it is absolutely indicated for carcinoid syndrome, glucagonoma and VIPoma. At present, longacting release somatostatin analogs are preferably used because they lengthen the time to tumor progression in patients with functionally active and inactive endocrine tumors, whereas multiple injections are avoided.[25,42]Daily oral administration of everolimus with or without co-administration of long-acting release octreotide has shown promising results in phase-II trials in patients with advanced PETs after failure of prior chemotherapy.[43]Ge fi tinib, a tyrosine kinase inhibitor, is experimentally veri fi ed in PETs, and acts by targeting the epidermal growth factor receptor.[44]Radiolabeled analogs of somatostatin can also be targeted against residual tumor cells in order to restrict their growth, proliferation, and secretory activity.[45]Some newer biological therapies are currently being evaluated in clinical trials.[46,47]

Table 1. Summary of surgical options and their results

In metastatic PETs, an aggressive multimodal therapy is recommended to relieve symptoms and extend survival.[48]Tables 1 and 2 summarize the results of different surgical options and additional local destructive techniques.

Prophylactic cholecystectomy

The role of prophylactic cholecystectomy has been clari fi ed, and this operation is considered necessary for an advanced neuroendocrine tumor.[5]Somatostatin analogs may induce gallstone disease in up to 50% of cases, while chemoembolization has a high risk for cholecystitis occurrence.

In conclusion, the management of metastatic disease in PETs is feasible today, and among different approaches radical excision or debulking excision for well-differentiated carcinomas is the cornerstone of treatment. Modern management can offer remarkable improvements, including symptom relief and control of metastasis even in more advanced cases.

Funding: None.

Ethical approval: Not needed.

Contributors: PTE wrote the main body of the article with the help of PK, SNG and PET under the supervision of SAK. PET provided advice on literature data and their interpretation, while SAK provided advice on surgical aspects. PTE is the guarantor.

Competing interest: No bene fi ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 Zhang M, Xu X, Shen Y, Hu ZH, Wu LM, Zheng SS. Clinical experience in diagnosis and treatment of glucagonoma syndrome. Hepatobiliary Pancreat Dis Int 2004;3:473-475.

2 Ekeblad S. Islet cell tumours. Adv Exp Med Biol 2010;654:771-789.

3 Sakurai A, Katai M, Yamashita K, Mori J, Fukushima Y,Hashizume K. Long-term follow-up of patients with multiple endocrine neoplasia type 1. Endocr J 2007;54:295-302.

4 Moayedoddin B, Booya F, Wermers RA, Lloyd RV, Rubin J,Thompson GB, et al. Spectrum of malignant somatostatinproducing neuroendocrine tumors. Endocr Pract 2006;12:394-400.

5 Falconi M, Bettini R, Boninsegna L, Crippa S, Butturini G,Pederzoli P. Surgical strategy in the treatment of pancreatic neuroendocrine tumors. JOP 2006;7:150-156.

6 Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011;30:3-7.

7 Oberg K. Pancreatic endocrine tumors. Semin Oncol 2010;37:594-618.

8 House MG, Schulick RD. Endocrine tumors of the pancreas.Curr Opin Oncol 2006;18:23-29.

9 Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am 2009;89:1105-1121.

10 Zerbi A, Falconi M, Rindi G, Delle Fave G, Tomassetti P,Pasquali C, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol 2010;105:1421-1429.

11 Casadei R, Ricci C, Pezzilli R, Campana D, Tomassetti P, Calculli L, et al. Are there prognostic factors related to recurrence in pancreatic endocrine tumors? Pancreatology 2010;10:33-38.

12 Goh BK, Chow PK, Tan YM, Cheow PC, Chung YF, Soo KC, et al. Validation of fi ve contemporary prognostication systems for primary pancreatic endocrine neoplasms: results from a single institution experience with 61 surgically treated cases. ANZ J Surg 2011;81:79-85.

13 Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G,Cassetta S, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 2005;12:1083-1092.

14 Tomassetti P, Campana D, Piscitelli L, Casadei R, Santini D,Nori F, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol 2005;16:1806-1810.

15 Long KB, Srivastava A, Hirsch MS, Hornick JL. PAX8 Expression in well-differentiated pancreatic endocrine tumors: correlation with clinicopathologic features and comparison with gastrointestinal and pulmonary carcinoid tumors. Am J Surg Pathol 2010;34:723-729.

16 Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, et al. Pancreatic endocrine tumors: expression pro fi ling evidences a role for AKT-mTOR pathway. J Clin Oncol 2010;28:245-255.

17 Zhang L, Lohse CM, Dao LN, Smyrk TC. Proposed histopathologic grading system derived from a study of KIT and CK19 expression in pancreatic endocrine neoplasm.Hum Pathol 2011;42:324-331.

18 Chetty R, Serra S, Asa SL. Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors. Am J Surg Pathol 2008;32:413-419.

19 Kianmanesh R, O'Toole D, Sauvanet A, Ruszniewski P,Belghiti J. Surgical treatment of gastric, enteric pancreatic endocrine tumors. Part 2. treatment of hepatic metastases. J Chir (Paris) 2005;142:208-219.

20 Peplinski GR, Norton JA. Gastrointestinal endocrine cancers and nodal metastasis: biologic signi fi cance and therapeutic implications. Surg Oncol Clin N Am 1996;5:159-171.

21 Azimuddin K, Chamberlain RS. The surgical management of pancreatic neuroendocrine tumors. Surg Clin North Am 2001;81:511-525.

22 Mignon M. Natural history of neuroendocrine enteropancreatic tumors. Digestion 2000;62:51-58.

23 Jensen RT. Carcinoid and pancreatic endocrine tumors:recent advances in molecular pathogenesis, localization, and treatment. Curr Opin Oncol 2000;12:368-377.

24 Wiedenmann B, Jensen RT, Mignon M, Modlin CI, Skogseid B, Doherty G, et al. Preoperative diagnosis and surgical management of neuroendocrine gastroenteropancreatic tumors: general recommendations by a consensus workshop.World J Surg 1998;22:309-318.

25 Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg 2006;93:264-275.

26 de Herder WW, Krenning EP, Van Eijck CH, Lamberts SW. Considerations concerning a tailored, individualized therapeutic management of patients with (neuro)endocrine tumours of the gastrointestinal tract and pancreas. Endocr Relat Cancer 2004;11:19-34.

27 Modlin IM, Lewis JJ, Ahlman H, Bilchik AJ, Kumar RR.Management of unresectable malignant endocrine tumors of the pancreas. Surg Gynecol Obstet 1993;176:507-518.

28 Fendrich V, Bartsch DK. Surgical treatment of gastrointestinal neuroendocrine tumors. Langenbecks Arch Surg 2011;396:299-311.

29 Máthé Z, Tagkalos E, Paul A, Molmenti EP, Kóbori L, Fouzas I, et al. Liver transplantation for hepatic metastases of neuroendocrine pancreatic tumors: a survival-based analysis.Transplantation 2011;91:575-582.

30 Chung JC, Choi DW, Jo SH, Heo JS, Choi SH, Kim YI.Malignant nonfunctioning endocrine tumors of the pancreas:predictive factors for survival after surgical treatment. World J Surg 2007;31:579-585.

31 Ghaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ.Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg 2008;12:382-393.

32 Schneider R, Waldmann J, Swaid Z, Ramaswamy A, Fendrich V, Bartsch DK, et al. Calcitonin-secreting pancreatic endocrine tumors: systematic analysis of a rare tumor entity.Pancreas 2011;40:213-221.

33 Fernández-Cruz L, Blanco L, Cosa R, Rendón H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors? World J Surg 2008;32:904-917.

34 Zhao YP, Zhan HX, Zhang TP, Cong L, Dai MH, Liao Q,et al. Surgical management of patients with insulinomas:Result of 292 cases in a single institution. J Surg Oncol 2011;103:169-174.

35 Ho AS, Picus J, Darcy MD, Tan B, Gould JE, Pilgram TK,et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol 2007;188:1201-1207.

36 de Baere T, Deschamps F, Teriitheau C, Rao P, Conengrapht K, Schlumberger M, et al. Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumors with doxorubicin-eluting beads: preliminary results. J Vasc Interv Radiol 2008;19:855-861.

37 Seifert JK, Cozzi PJ, Morris DL. Cryotherapy for neuroendocrine liver metastases. Semin Surg Oncol 1998;14: 175-183.38 Okada T, Nishimura T, Nakamura M, Sakata K, Katou A,Setoguchi M, et al. Non-functional pancreatic endocrine carcinoma with multiple liver metastases--a case report. Gan To Kagaku Ryoho 2010;37:2370-2372.

39 Akyildiz HY, Mitchell J, Milas M, Siperstein A, Berber E.Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery 2010;148:1288-1293.

40 Pfeifer AK, Gregersen T, Gr?nb?k H, Hansen CP, Müller-Brand J, Herskind Bruun K, et al. Peptide Receptor Radionuclide Therapy with Y-DOTATOC and (177)Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland. Neuroendocrinology 2011;93:189-196.

41 Nisa L, Savelli G, Giubbini R. Yttrium-90 DOTATOC therapy in GEP-NET and other SST2 expressing tumors: a selected review. Ann Nucl Med 2011;25:75-85.

42 Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P,Wied M, et al. Placebo-controlled, double-blind, prospective,randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-4663.

43 Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P,Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69-76.

44 H?pfner M, Sutter AP, Gerst B, Zeitz M, Scherübl H. A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by ge fi tinib (ZD1839). Br J Cancer 2003;89:1766-1775.

45 Biliotti G, Martini F, Vaggelli L, Messerini L, Colagrande S,Pupi A, et al. Multiple effects of somatostatin analogs veri fi ed in three cases of metastasized neuroendocrine tumors of the gastroenteropancreatic system. Tumori 2006;92:170-174.

46 Faivre S, Sablin MP, Dreyer C, Raymond E. Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors. Endocrinol Metab Clin North Am 2010;39:811-826.

47 Zarebczan B, Chen H. Signaling mechanisms in neuroendocrine tumors as targets for therapy. Endocrinol Metab Clin North Am 2010;39:801-810.

48 Teh SH, Deveney C, Sheppard BC. Aggressive pancreatic resection for primary pancreatic neuroendocrine tumor: is it justi fi able? Am J Surg 2007;193:610-613.

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved.

DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery.

RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important.Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time,but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors.The combination of chemoembolization and systemic chemotherapy results in better response and survival rates.Other local destructive techniques include ethanol injection,cryotherapy and radiofrequency ablation.

CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases.

Author Af fi liations: Second Surgical Propedeutical Department, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki,Konstantinopoulos 49, 54642 Thessaloniki, Greece (Pavlidis TE, Psarras K, Symeonidis NG, Pavlidis ET and Sakantamis AK)

Theodoros E Pavlidis, Professor, A Samothraki 23,542 48 Thessaloniki, Greece (Tel: +302310-992861; Fax: +302310-992932;Email: pavlidth@med.auth.gr)

? 2011, Hepatobiliary Pancreat Dis Int. All rights reserved.

January 10, 2011

Accepted after revision March 23, 2011