Clin J Gastroenterol (2013) 6:496–499 DOI 10.1007/s12328-013-0437-3
CASE REPORT
Hepatic arterial infusion combined with systemic chemotherapy induced complete response of metachronous liver metastases after resection of pancreatic insulinoma Yuki Kiyozumi • Hiroshi Takamori • Osamu Nakahara • Yoshiaki Ikuta • Akira Chikamoto • Toru Beppu • Hideo Baba
Received: 24 April 2013 / Accepted: 7 November 2013 / Published online: 20 November 2013 Ó Springer Japan 2013
Abstract Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery. Keywords Pancreatic insulinoma Hepatic arterial infusion Chemotherapy
Introduction Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs), with an estimated incidence of 1–3 per million individuals per year [1].
Y. Kiyozumi (&) H. Takamori O. Nakahara Y. Ikuta A. Chikamoto T. Beppu H. Baba Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan e-mail: [email protected]
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Insulinomas are characteristically small tumors, and less than 10 % of patients with distant metastases have a median survival of less than 2 years [2]. We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases following hepatic arterial infusion combined with systemic chemotherapy.
Case report A 58-year-old woman was admitted to our hospital following loss of consciousness. Laboratory data documented hypoglycemia with 48 mg/dl, and the symptoms were relieved following intravenous glucose administration on admission. She has no past history or family history of these symptoms. Her BMI was 20.5. Serum insulin and C-peptide levels were elevated to 23.6 l/ml and 3.41 ng/ ml, respectively. Other laboratory data were within normal ranges. Ultrasonography revealed a tumor located in the pancreatic body and tail. Enhanced computed tomography (CT) also revealed a hypoenhancing solid tumor of 23 9 80 mm (Fig. 1). The pancreatic tumor showed a high uptake of FDG on FDG-PET/CT, but no distant metastases were observed during imaging. The patient underwent distal pancreatectomy following diagnosis of insulinoma. Histological examination of the resected specimen diagnosed insulinoma, NET G2 with 10 % of the MIB-1 index, according to the WHO 2010 classification [3] (Fig. 2). Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery (Fig. 3a), but the patient had no symptoms associated with hypoglycemia at this time. Serum insulin and C-peptide levels were decreased to 1.6 l/ml and 0.8 ng/ml at this point. Multiple liver metastases were
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Fig. 1 CT showed a hypoenhancing solid tumor (arrow) sized 23 9 80 mm in the pancreatic body and tail. a Arterial phase; b venous phase
Fig. 2 Histological examination showed a well-differentiated endocrine tumor by H&E staining (a) with venous invasion (b). Immunohistochemical studies showed that insulin was partially but
strongly stained (c), and glucagon was diffusely but weakly stained (d). The MIB-1 index was determined to be 10 % (e)
confirmed by computed tomography during arterial portography combined with computed tomography-assisted hepatic arteriography (CTAP and CTHA) (Fig. 3b, c). Metastases were not observed in any other organs besides the liver during imaging; therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. 5-FU was administered at a dose of 250 mg/day on days 1 to 5 every week by continuous hepatic arterial infusion using the arterial port. Gemcitabine was infused intravenously for 30 min at a dose of 1000 mg/m2 once per week for 3 consecutive weeks of every 4 weeks as one cycle. MRI was performed
every 4 weeks to evaluate response, and we found complete absence of all liver metastatic nodules after 11 cycles of chemotherapy (Fig. 3d). We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery.
Discussion More than 90 % of insulinomas are non-metastatic at presentation and can be surgically cured [4]. Less than 10 % of patients with distant metastases have a median
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Fig. 3 SPIO-MRI (T2 weighted) showed multiple metastatic lesions suspected (arrows) 3 months after surgery (a). CTHA also showed multiple enhanced lesions (arrows) (b), which were hypoattenuated (arrows) on CTAP (c). No liver metastases were detected by MRI (T2 weighted) after 11 cycles of chemotherapy (d)
survival of less than 24 months [2]. There are several reported predictive factors for metastases, including tumor size, tumor grading, staging and Ki-67 index of more than 2 % [5]. Insulinomas larger than 3 cm account for less than 5 % of them [6]. Bosman et al. described that giant insulinomas are characterized by focal expression of high rates of liver metastases. Therefore, long-term follow-up is required to detect recurrences [7]. In this case, the tumor size was more than 2 cm, and the Ki-67 index was also more then 2 %. Therefore, critical observation for distant metastases was required. In this case, there were no symptoms of hypoglycemia because we found metastatic lesions before symptoms appeared. We absolutely needed to perform a biopsy and acquire the histological diagnosis for metastatic liver lesions. However, we diagnosed liver metastasis from radiography alone, because we found that needle biopsy is quiet difficult in multiple small metastatic lesions. Usually, insulinomas are hypervascular and demonstrate a greater degree of enhancement during the arterial phase. However, this case showed hypoenhanced primary tumor of the pancreas. On the other hand, CTHA revealed multiple enhanced lesions. We considered the reason might
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have been the histological type and unusual size. The percentages of necrotic tissues in this tumor were higher than in typical insulinomas of normal size. Therefore, it was possible that this difference in tissue type was caused by the different types of enhancement in these images. Since only few reports exist on this, it could not be clearly determined. Chemotherapies with streptozocin combined with 5-FU and/or doxorubicin have been used in patients with metastatic insulinomas. These combination treatments result in tumor response in 6–70 % of patients with PNETs, including insulinomas, although specific information on malignant insulinomas is lacking. In this case, we performed 5-FU hepatic arterial infusion combined with systemic gemcitabine for metachronous liver metastases of pancreatic insulinoma. We have previously reported that this combined chemotherapy is feasible and effective for unresectable pancreatic cancer and results in a median survival of 14 months and a 1-year survival rate of 50.9 % [8]. As far as we know, this case is the first report of complete response of liver metastases using this combined cytotoxic chemotherapy, resulting in 5-year survival without new lesions.
Clin J Gastroenterol (2013) 6:496–499
Thus, our study indicates that this combined chemotherapy is a useful option in the treatment of liver metastases secondary to insulinomas. Disclosures Conflict of Interest: The authors declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
References 1. Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int. 2010;9:234–41.
499 2. Danforth DN Jr, Gorden P, Brennan MF. Metastatic insulinsecreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery. 1984;96:1027–37. 3. Klistra DS, Arnold R, Capella C, Hruban RH, Kloppel G, Komminoth P, et al. Neuroendocrine neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. Lyon: IAPC; 2010. p. 322–6. 4. de Herder WW, Niederle B, Scoazec JY, Pauwels S, Koppel G, Falconi M, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84:183–8. 5. de Herwer WW, van Schaik E, Kwekkeboom D, Feelders RA. New therapeutic options for metastatic malignant insulinomas. Clin Endocrinol. 2011;75:277–84. 6. Benedetto L, Riccardo C, Valentina F, Yolanda Q, Hipolito D, Hipolito D, et al. Giant pancreatic insulinoma. The bigger the worse? Report of two cases and literature review. Int J Surg Case Rep. 2013;4(4):265–8. 7. Callacondo D, Arenas JL, Ganoza AJ, Rojas-Camayo J, QuesadaOlarte J, Robledo H. Giant insulinoma: a report of 3 cases and review of the literature. Pancreas. 2013;42(8):1323–32. doi:10. 1097/MPA.0b013e318292006a 8. Takamori H, Kanemitsu K, Tsuji T, Tanaka H, Chikamoto A, Nakahara O, et al. 5-fluorouracil intra-arterial infusion combined with systematic gemcitabine for unresectable pancreatic cancer. Pancreas. 2005;30:223–36.
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CASE REPORT
Hepatic arterial infusion combined with systemic chemotherapy induced complete response of metachronous liver metastases after resection of pancreatic insulinoma Yuki Kiyozumi • Hiroshi Takamori • Osamu Nakahara • Yoshiaki Ikuta • Akira Chikamoto • Toru Beppu • Hideo Baba
Received: 24 April 2013 / Accepted: 7 November 2013 / Published online: 20 November 2013 Ó Springer Japan 2013
Abstract Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery. Keywords Pancreatic insulinoma Hepatic arterial infusion Chemotherapy
Introduction Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs), with an estimated incidence of 1–3 per million individuals per year [1].
Y. Kiyozumi (&) H. Takamori O. Nakahara Y. Ikuta A. Chikamoto T. Beppu H. Baba Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan e-mail: [email protected]
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Insulinomas are characteristically small tumors, and less than 10 % of patients with distant metastases have a median survival of less than 2 years [2]. We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases following hepatic arterial infusion combined with systemic chemotherapy.
Case report A 58-year-old woman was admitted to our hospital following loss of consciousness. Laboratory data documented hypoglycemia with 48 mg/dl, and the symptoms were relieved following intravenous glucose administration on admission. She has no past history or family history of these symptoms. Her BMI was 20.5. Serum insulin and C-peptide levels were elevated to 23.6 l/ml and 3.41 ng/ ml, respectively. Other laboratory data were within normal ranges. Ultrasonography revealed a tumor located in the pancreatic body and tail. Enhanced computed tomography (CT) also revealed a hypoenhancing solid tumor of 23 9 80 mm (Fig. 1). The pancreatic tumor showed a high uptake of FDG on FDG-PET/CT, but no distant metastases were observed during imaging. The patient underwent distal pancreatectomy following diagnosis of insulinoma. Histological examination of the resected specimen diagnosed insulinoma, NET G2 with 10 % of the MIB-1 index, according to the WHO 2010 classification [3] (Fig. 2). Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3 months after surgery (Fig. 3a), but the patient had no symptoms associated with hypoglycemia at this time. Serum insulin and C-peptide levels were decreased to 1.6 l/ml and 0.8 ng/ml at this point. Multiple liver metastases were
Clin J Gastroenterol (2013) 6:496–499
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Fig. 1 CT showed a hypoenhancing solid tumor (arrow) sized 23 9 80 mm in the pancreatic body and tail. a Arterial phase; b venous phase
Fig. 2 Histological examination showed a well-differentiated endocrine tumor by H&E staining (a) with venous invasion (b). Immunohistochemical studies showed that insulin was partially but
strongly stained (c), and glucagon was diffusely but weakly stained (d). The MIB-1 index was determined to be 10 % (e)
confirmed by computed tomography during arterial portography combined with computed tomography-assisted hepatic arteriography (CTAP and CTHA) (Fig. 3b, c). Metastases were not observed in any other organs besides the liver during imaging; therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. 5-FU was administered at a dose of 250 mg/day on days 1 to 5 every week by continuous hepatic arterial infusion using the arterial port. Gemcitabine was infused intravenously for 30 min at a dose of 1000 mg/m2 once per week for 3 consecutive weeks of every 4 weeks as one cycle. MRI was performed
every 4 weeks to evaluate response, and we found complete absence of all liver metastatic nodules after 11 cycles of chemotherapy (Fig. 3d). We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7 years after surgery.
Discussion More than 90 % of insulinomas are non-metastatic at presentation and can be surgically cured [4]. Less than 10 % of patients with distant metastases have a median
123
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Clin J Gastroenterol (2013) 6:496–499
Fig. 3 SPIO-MRI (T2 weighted) showed multiple metastatic lesions suspected (arrows) 3 months after surgery (a). CTHA also showed multiple enhanced lesions (arrows) (b), which were hypoattenuated (arrows) on CTAP (c). No liver metastases were detected by MRI (T2 weighted) after 11 cycles of chemotherapy (d)
survival of less than 24 months [2]. There are several reported predictive factors for metastases, including tumor size, tumor grading, staging and Ki-67 index of more than 2 % [5]. Insulinomas larger than 3 cm account for less than 5 % of them [6]. Bosman et al. described that giant insulinomas are characterized by focal expression of high rates of liver metastases. Therefore, long-term follow-up is required to detect recurrences [7]. In this case, the tumor size was more than 2 cm, and the Ki-67 index was also more then 2 %. Therefore, critical observation for distant metastases was required. In this case, there were no symptoms of hypoglycemia because we found metastatic lesions before symptoms appeared. We absolutely needed to perform a biopsy and acquire the histological diagnosis for metastatic liver lesions. However, we diagnosed liver metastasis from radiography alone, because we found that needle biopsy is quiet difficult in multiple small metastatic lesions. Usually, insulinomas are hypervascular and demonstrate a greater degree of enhancement during the arterial phase. However, this case showed hypoenhanced primary tumor of the pancreas. On the other hand, CTHA revealed multiple enhanced lesions. We considered the reason might
123
have been the histological type and unusual size. The percentages of necrotic tissues in this tumor were higher than in typical insulinomas of normal size. Therefore, it was possible that this difference in tissue type was caused by the different types of enhancement in these images. Since only few reports exist on this, it could not be clearly determined. Chemotherapies with streptozocin combined with 5-FU and/or doxorubicin have been used in patients with metastatic insulinomas. These combination treatments result in tumor response in 6–70 % of patients with PNETs, including insulinomas, although specific information on malignant insulinomas is lacking. In this case, we performed 5-FU hepatic arterial infusion combined with systemic gemcitabine for metachronous liver metastases of pancreatic insulinoma. We have previously reported that this combined chemotherapy is feasible and effective for unresectable pancreatic cancer and results in a median survival of 14 months and a 1-year survival rate of 50.9 % [8]. As far as we know, this case is the first report of complete response of liver metastases using this combined cytotoxic chemotherapy, resulting in 5-year survival without new lesions.
Clin J Gastroenterol (2013) 6:496–499
Thus, our study indicates that this combined chemotherapy is a useful option in the treatment of liver metastases secondary to insulinomas. Disclosures Conflict of Interest: The authors declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
References 1. Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN. Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int. 2010;9:234–41.
499 2. Danforth DN Jr, Gorden P, Brennan MF. Metastatic insulinsecreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery. 1984;96:1027–37. 3. Klistra DS, Arnold R, Capella C, Hruban RH, Kloppel G, Komminoth P, et al. Neuroendocrine neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. Lyon: IAPC; 2010. p. 322–6. 4. de Herder WW, Niederle B, Scoazec JY, Pauwels S, Koppel G, Falconi M, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006;84:183–8. 5. de Herwer WW, van Schaik E, Kwekkeboom D, Feelders RA. New therapeutic options for metastatic malignant insulinomas. Clin Endocrinol. 2011;75:277–84. 6. Benedetto L, Riccardo C, Valentina F, Yolanda Q, Hipolito D, Hipolito D, et al. Giant pancreatic insulinoma. The bigger the worse? Report of two cases and literature review. Int J Surg Case Rep. 2013;4(4):265–8. 7. Callacondo D, Arenas JL, Ganoza AJ, Rojas-Camayo J, QuesadaOlarte J, Robledo H. Giant insulinoma: a report of 3 cases and review of the literature. Pancreas. 2013;42(8):1323–32. doi:10. 1097/MPA.0b013e318292006a 8. Takamori H, Kanemitsu K, Tsuji T, Tanaka H, Chikamoto A, Nakahara O, et al. 5-fluorouracil intra-arterial infusion combined with systematic gemcitabine for unresectable pancreatic cancer. Pancreas. 2005;30:223–36.
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