SEARCH

SEARCH BY CITATION

Keywords:

  • Islet autotransplantation;
  • renal cell carcinoma;
  • pancreatectomy;
  • pancreatic metastases

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

Pancreatic metastases from renal cell carcinoma (RCC) may have a chronic and highly indolent course, and may be resected for cure after considerable delay following treatment of the primary tumor, in contrast to other more common pancreatic tumors. Surgical resection is the treatment of choice, which may lead to postpancreatectomy diabetes mellitus in the case of extensive resection. We present a 70-year-old patient with multifocal pancreatic metastases from RCC causing obstructive jaundice. A total pancreatectomy was required to excise two distant tumors in the head and tail of the pancreas, together with a segment VI liver resection. An autologous islet transplant (AIT) prepared from the central, uninvolved pancreas was carried out to prevent postpancreatectomy diabetes. The patient was rendered insulin-free and remains so with excellent glycemic control for 1 year of follow-up, and there is no evidence of tumor recurrence. The patient has been treated with adjuvant sunitinib to minimize risk of further recurrence. In conclusion, AIT after pancreatectomy may represent a useful option to treat patients with metastatic RCC. A critical component of this approach was dependent upon elaborate additional testing to exclude contamination of the islet preparation by cancerous cells.


Abbreviations
AIT

autologous islet transplantation

CT

computed tomography

IEQ

islet equivalents

RCC

renal cell carcinoma

US

abdominal ultrasound.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

The natural history of renal cell carcinoma (RCC) has a high 5-year survival (up to 95%) when the tumor is limited to the kidney [1, 2]. In patients with RCC, up to 30% have metastases at presentation, and 40−50% will develop widespread metastatic disease over time [3]. The long-term (5-year) survival rate is 10−15% once metastases have spread [1].

Pancreatic metastases are generally uncommon, with an incidence varying from 2% to 5%. However, the pancreas is a target site for metastases from carcinoma of the kidney, and may present typically after a prolonged delay after nephrectomy [1, 3, 4]. Pancreatic metastases from RCC have a high resectability rate compared with other more common pancreatic tumors [3]. However, these lesions may be multifocal in 30% of the cases and require more radical resection resulting in “brittle” diabetes mellitus, which may be difficult to manage. Autologous islet transplantation (AIT) after near-total or total pancreas resection offers a potential means to preserve endocrine function, provided this does not compromise tumor resection margins [5-8].

Islet autotransplantation was first performed in 1977 at the University of Minnesota, allowing the patient to remain insulin free until his death 6 years later [8, 9]. Since then, more than 500 AIT have been performed, mainly for patients undergoing total pancreatectomy for chronic pancreatitis [5, 9]. In such patients, approximately 70% of insulin independence has been achieved at 3 years after AIT if more than 5000 islet equivalents (IEQ) are transplanted [9-11].

Islet autotransplantation has been utilized for a selected series of benign pancreatic diseases, including pseudocysts, cystic neoplasms, insulinomas and neuroendocrine tumors [10, 12, 13]. Balancing the potential benefit of preventing surgical diabetes against the oncologic risk of inadvertently embolizing tumor cells poses an interesting dilemma. We present the case report and metabolic studies of a patient who underwent AIT after total pancreatectomy for multifocal RCC pancreatic metastases.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

A 70-year-old female with history of rheumatoid arthritis had a remote diagnosis of RCC 15 years prior to admission, treated at that time by left radical nephrectomy. She presented with a 2-week history of malaise, pruritus and obstructive jaundice with elevated transaminase, bilirubin and alkaline phosphatase. The previous nephrectomy pathology confirmed RCC stage II (T2, N0, M0) resected with negative margins and uninvolved lymph nodes, and no further adjuvant treatment had been given. Physical examination revealed marked jaundice with a palpable Courvoisier's gallbladder. Pancreatic tumor markers were normal (CA 19.9 < 1 kU/L and CEA 1.9 μg/L). A pancreatic protocol contrast-enhanced computed tomography (CT, 1.25 mm slice reconstructions) revealed multifocal, hypervascular pancreatic lesions in the uncinate process of the pancreas (32 mm diameter) with distal biliary obstruction (Figure 1B), and in the pancreatic tail (13 mm diameter; Figure 1C), both with central diminished attenuation. No peri-pancreatic lymphadenopathy was identified. Specifically there was no evidence of tumor or pancreatic ductal dilatation within the central pancreatic body, which appeared to be normal on CT. Within the liver, a 24 mm similar hypervascular lesion was identified within segment 6, highly suspicious for metastatic focus (Figure 1A). The liver lesion was biopsied by fine needle ultrasound-guided approach, and demonstrated clear cells consistent with RCC primary origin. A chest CT revealed no additional metastatic disease, and the pancreatic and liver disease was therefore potentially resectable.

image

Figure 1. Computed tomography imaging preoperatively demonstrating hypervascular metastatic renal cell carcinoma deposits in (A) Segment 6 liver; (B) Uncinate process pancreas with biliary obstruction, and (C) Pancreatic tail.

Download figure to PowerPoint

Laparotomy did not reveal any additional pancreatic, hepatic or peritoneal disease. A high-resolution intra-operative contact ultrasound probe was used to examine the entire pancreas after complete pancreatic mobilization, to rule out occult, additional parenchymal lesions. Based on RCC involvement of the uncinate and tail of the pancreas (Figure 2), with sparing of the central pancreas, we carried out a total pancreatectomy with splenectomy. Intra-operatively, we transected both the pancreatic neck and the distal pancreatic body, and confirmed by frozen-section pathology that both proximal and distal margins on the pancreatic body were uninvolved with RCC. The tumor-free central pancreatic body was then sent for processing for AIT. During this period, we maintained the pancreatic body vasculature intact in order to maximize islet oxygenation and viability (Figure 3A). The central pancreas weighed 38.8 g. On the back-table, the pancreatic duct was cannulated (Figure 3B), and the splenic artery was flushed with 1 L of chilled HTK solution (Custodiol, Methapharm, Brantford, ON, Canada).

image

Figure 2. Intraoperative photograph of renal cell carcinoma in the pancreatic tail.

Download figure to PowerPoint

image

Figure 3. (A) Intraoperative photograph of preserved vascular flow in the central pancreas after both Whipple and distal pancreatic resection, with the goal being to maintain islet oxygenation and viability up till the point of explantation. (B) Back-table cannulation of the pancreatic duct prior to digestion and islet isolation.

Download figure to PowerPoint

The islet isolation method was similar to the standard digestion using the Ricordi method as used for allogeneic transplantation [14, 15]. Enzymatic digestion used CIzyme Collagenase HA (2196 Wunsch Units; VitaCyte, Indianapolis, IN) and CIzyme Thermolysin (828 000 units; VitaCyte). After digestion 3.9 g of tissue remained in the chamber.

In this case, islet purification was performed to further minimize the risk of embolization of pancreatic exocrine tissue. It consisted of a combination of Biocoll and University of Wisconsin solution to make a continuous density gradient [16]. There were only 1056 IEQ left in the less pure layer. The high purity (55%) layer yielded 268 195 IEQ (6192 IEQ/g of pancreas, 4400 IEQ/kg of recipient's body weight), in a packed cell volume of 2.0 mL. No tissue samples were submitted for pathology analysis.

While the islets were being prepared the proximal pancreatectomy was completed with the subsequent reconstruction (hepaticojejunostomy, roux-en-Y pylorus-preserving gastrojejunostomy and entero-enterostomy). The right lobe of the liver was mobilized and an anatomical resection was carried out of the segment 6 lesion. Finally, a 9-French dual lumen catheter (Broviac, Bard Canada Inc., Oakville, ON, Canada) was preflushed with heparinized saline and secured within the stump of the splenic vein and advanced to the portal confluence to allow infusion of the islet preparation together with simultaneous portal pressure monitoring. The patient tolerated the transplant procedure well and the portal pressure remained within normal range (mean portal pressure 16.6 mmHg) throughout the islet infusion. Heparin (Heparin Sodium Injection, Sandoz Canada, Boucherville, QC, Canada) was used systemically (400 U/h IV) and also within the islet infusion bag (70 U/kg). No blood products were required.

Postoperative recovery was entirely uneventful. A Doppler ultrasound on the first postoperative day confirmed portal venous patency. Glycemic control remained within the normal range throughout hospitalization (6–8 mmol/L). The final pathology confirmed RCC metastases with clear cell change within the uncinate, tail and segment 6 liver, all resected with negative margins. The cells were positive for vimentin and CD10, but negative for p53. The patient was discharged on postoperative Day 13 with close follow-up every 3 months. She remains insulin-free with excellent glycemic control (fasting glucose 5.2 mmol/L, c-peptide 0.48 nmol/L, HbA1c 5.3%), and is tumor free at almost 1 year of follow-up. She has received adjuvant sunitinib (Sutent, Pfizer Canada, Kirkland, QC, Canada) chemotherapy to further reduce risk of additional recurrent disease.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

Extended pancreatic resections can provide curative treatment of both primary and metastatic pancreatic tumors. Total pancreatectomy with surgical removal of the entire islet cell mass leads to surgical diabetes that, in the absence of insulin and counter-regulatory glucagon hormonal balance, results in difficult to control diabetes with substantial risk of severe hypoglycemia [5, 9].

Although autologous islet transplantation has successfully prevented surgical diabetes in patients with chronic pancreatitis, concern of inadvertent infusion of occult malignant cells in the islet preparation has restricted application of this approach in patients with underlying malignancies [10, 17]. A case report of total pancreatectomy with AIT in the setting of pancreatic head adenocarcinoma has been described previously [17].

To our knowledge the current case represents the first report of AIT after total pancreatectomy for multifocal pancreatic metastases for RCC. The rationale was to preserve quality of life and prevent glycemic lability in a patient with an indolent but malignant metastatic disease, with low risk of inadvertent tumoral embolization to the liver. Since the tumor occurred in two disparate but discrete locations in the uncinate and tail of the pancreas, the option of localized resection was not reasonable. The alternative option of Whipple pancreaticoduodenectomy combined with distal pancreatic resection would have had added risk of pancreatic fistula. Application of AIT allowed preservation of insulin and glucagon secretory reserve and has resulted in prolonged and sustained independence from insulin in a 70-year-old lady that would otherwise have developed “brittle” diabetes.

The islet isolation performed in this particular case resulted in high islet yield from a nonfibrotic pancreas. Islet yields up to 7000 IEQs/g are exceptional in autoislet isolation as the main indication for the procedure is in patients with chronic pancreatitis, but may occur occasionally in islet allotransplantation.

Although all evident foci of metastatic tumoral deposits were radically resected with negative margins at surgery, we cannot rule out with absolute certainty the possibility of malignant cell foci within the final islet preparation. Specific precautions to minimize this risk included (a) high resolution preoperative imaging; (b) selection of a metastatic tumor of known biology and very indolent course; (c) intraoperative contact high-resolution pancreatic ultrasound to rule out smaller pancreatic lesions in the central pancreas; (d) frozen section interpretation of resection margins to be sure the central pancreas was not involved with infiltrative tumor and (e) deliberate application of islet purification steps in the autologous islet preparation process to further minimize islet contamination with exocrine pancreatic elements. Perhaps detection of VHL and PBRM1 mutations within the cell preparation could also have been used to rule out presence of residual RCC cells, but this was not used in this case [18-20].

With 1 year of follow-up, and combined with adjuvant sunitinib and serial imaging, there has been no evidence of residual or recurrent metastatic disease, and the patient remains insulin independent without risk of hypoglycemia. Since this patient also presented with a liver metastasis, we caution that if she were to develop further liver metastases, we would be unable to discern whether the AIT process would be contributory. We suggest that AIT provides an additional tool in the armamentarium for the pancreatic surgeon dealing with complex but indolent malignant pancreatic lesions. Further cellular screen tools would be critically important to minimize risk of inadvertent embolization of malignant cells.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References
  • 1
    Ballarin R, Spaggiari M, Cautero N, et al. Pancreatic metastases from renal cell carcinoma: The state of the art. World J Gastroenterol 2011; 17: 47474756.
  • 2
    Cho DC. Therapeutic challenges in advanced renal cell carcinoma. Clin Pract (Lond) 2013; 10: 3946.
  • 3
    Bassi C, Butturini G, Falconi M, Sargenti M, Mantovani W, Pederzoli P. High recurrence rate after atypical resection for pancreatic metastases from renal cell carcinoma. Br J Surg 2003; 90: 555559.
  • 4
    Aguayo-Albasini JL, Garcia-Garcia ML, Martin-Lorenzo JG, Cases-Baldo MJ, Campillo-Soto A, Mengual-Ballester M. Subtotal distal pancreatectomy for metachronous metastatic renal clear cell carcinoma. Rev Esp Enferm Dig 2012; 104: 613614.
  • 5
    Bellin MD, Beilman GJ, Dunn TB, et al. Islet autotransplantation to preserve beta cell mass in selected patients with chronic pancreatitis and diabetes mellitus undergoing total pancreatectomy. Pancreas 2013; 42: 317321. doi: 10.1097/MPA.0b013e3182681182
  • 6
    Bellin MD, Freeman ML, Schwarzenberg SJ, et al. Quality of life improves for pediatric patients after total pancreatectomy and islet autotransplant for chronic pancreatitis. Clin Gastroenterol Hepatol 2011; 9: 793799.
  • 7
    Brendle TA. Preventing surgically induced diabetes after total pancreatectomy via autologous islet cell reimplantation. AORN J 2010; 92: 169181; quiz 182−163.
  • 8
    Sutherland DE, Gruessner AC, Carlson AM, et al. Islet autotransplant outcomes after total pancreatectomy: A contrast to islet allograft outcomes. Transplantation 2008; 86: 17991802.
  • 9
    Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 2012; 214: 409424; discussion 424−406.
  • 10
    Ris F, Niclauss N, Morel P, et al. Islet autotransplantation after extended pancreatectomy for focal benign disease of the pancreas. Transplantation 2011; 91: 895901.
  • 11
    Webb MA, Illouz SC, Pollard CA, et al. Islet auto transplantation following total pancreatectomy: A long-term assessment of graft function. Pancreas 2008; 37: 282287.
  • 12
    Dong M, Parsaik AK, Erwin PJ, Farnell MB, Murad MH, Kudva YC. Systematic review and meta-analysis: Islet autotransplantation after pancreatectomy for minimizing diabetes. Clin Endocrinol 2011; 75: 771779.
  • 13
    Oberholzer J, Mathe Z, Bucher P, et al. Islet autotransplantation after left pancreatectomy for non-enucleable insulinoma. Am J Transplant 2003; 3: 13021307.
  • 14
    O'Gorman D, Kin T, Imes S, Pawlick R, Senior P, Shapiro AM. Comparison of human islet isolation outcomes using a new mammalian tissue-free enzyme versus collagenase NB-1. Transplantation 2010; 90: 255259.
  • 15
    Kawahara T, Kin T, Shapiro AM. A comparison of islet autotransplantation with allotransplantation and factors elevating acute portal pressure in clinical islet transplantation. J Hepatobiliary Pancreat Sci 2012; 19: 281288.
  • 16
    Barbaro B, Salehi P, Wang Y, et al. Improved human pancreatic islet purification with the refined UIC-UB density gradient. Transplantation 2007; 84: 12001203.
  • 17
    Forster S, Liu X, Adam U, Schareck WD, Hopt UT. Islet autotransplantation combined with pancreatectomy for treatment of pancreatic adenocarcinoma: A case report. Transplant Proc 2004; 36: 11251126.
  • 18
    Kapur P, Pena-Llopis S, Christie A, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: A retrospective analysis with independent validation. Lancet Oncol 2013; 14: 159167.
  • 19
    Taylor C, Craven RA, Harnden P, Selby PJ, Banks RE. Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. Int J Oncol 2012; 41: 12291240. doi: 10.3892/ijo.2012.1561
  • 20
    Xu X, Hou Y, Yin X, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 2012; 148: 886895.