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Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN)
Pancreatology 12 (2012) 423e427
Contents lists available at SciVerse ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Case report
Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN) S. Krug a, D.K. Bartsch b, M. Schober a, D. Librizzi c, A. Pfestroff c, M. Burbelko d, R. Moll e, P. Michl a,1, T.M. Gress a, *,1 a
Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany Department of Surgery, Philipps-University Marburg, Germany Department of Nuclear Medicine, Philipps-University Marburg, Germany d Department of Radiology, Philipps-University Marburg, Germany e Department of Pathology, Philipps-University Marburg, Germany b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 June 2012 Received in revised form 14 July 2012 Accepted 16 July 2012
Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1e5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (w90%) and normally present with unspecific symptoms. We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence. This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases. Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: SPN SIRT K-ras
1. Methodology We retrospectively analyzed a patient with SPN treated and in follow-up at our institution since 2002. Tumor tissue was analyzed immunohistochemically concerning expression of NSE, Vimentin, progesterone receptor, b-catenin, p53, Ki-67, a1-antrypsin, a1-antichymotrypsin, estrogene receptor, CD 117 and CD 10. Analyses were performed according to a standardized protocol using Leica-Bond-Max-Autostainer and the antibodies in the following dilutions: NSE: Dako 1:500; Vimentin: Dako 1:400; progesterone receptor: Leica/menarini 1:100; b-catenin: BD Transduction 1:50; p53: Leica/Menarini 1:50; Ki-67: Dako 1:100; a1-antitrypsin: Dako 1:50.000; a1-antichymotrypsin Dako 1:40.000; estrogene receptor: Leica/Menarini 1:100; CD 117: Dako 1:150; CD 10: Leica/ Menarini 1:20. * Corresponding author. Tel.: þ49 6421 5866460; fax: þ49 6421 5868922. E-mail address: [email protected] (T.M. Gress). 1 Shared last authorship.
High resolution melting analysis and pyrosequenzing detecting somatic mutations in exon 2 in codons 12 and 13 of the K-ras gene were done as previously described [1e3]. 2. Case report A 16-years-old Asian woman was referred to our hospital in 2002 for second opinion who had been diagnosed earlier this year with a metastatic solid pseudopapillary neoplasm of the pancreas (SPN) in Thailand. An initial surgical exploration performed in Bangkok in May 2002 had shown local irresectability. Furthermore, sequential palliative courses of chemotherapy consisting of gemcitabine followed by combination therapies with ifosfamide, etoposide and cisplatin had failed to show clinical response. Subsequently, the patient presented to our hospital for reevaluation. Since an aggressive surgical treatment was considered as the only promising strategy in this scenario, the patient was offered a second surgical exploration aiming at radical resection. In two sequential surgical interventions a pylorus-preserving partial duodenopancreatectomy
1424-3903/$ e see front matter Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2012.07.014
424
S. Krug et al. / Pancreatology 12 (2012) 423e427
Table 1 Histological and molecular findings of the SPN and the liver metastases in the reported patient in comparison to the literature [7,32,33]. Immunohistochemical examinations
Literature
Our patient
NSE Vimentin Progesterone receptor b-catenin
þ þ >80% positive þ
p53
>80% positive
MIB-1/Ki-67 a1-Antitrypsin a1-Antichymotrypsin Estrogene receptor CD 117 (c-kit) CD 10 EGFR K-ras
<1% þ <80% positive e 50% >80% positive Wt Wt
þ þ 10e20% positive >80% positive, nuclear and cell membrane very weakly heterogeneously positive (w30%) <1% þ heterogeneously w50% positive e e >80% positive e Codon 12 mutation
þ ¼ positive 80e100%; ¼ negative; wt ¼ wild-type.
with resection and allografting of the portal vein and right hemicolectomy as well as resection of 12 liver metastases were performed. The 20 12 10 cm measuring primary bulk and the multiple hepatic metastases showed typical histological features of SPN with Ki-67 <1% (Table 1). The histological assessment of the surgical specimens also revealed a hemangiosis carcinomatosa as well as mesenterial metastases, but initially no lymphatic involvement in sections of approximately 30 lymph nodes. High resolution melting analysis followed by pyrosequencing for K-ras mutations was done as previously described [1e3] and detected activating mutations in codon 12 (GGT > GAT). Following surgical resection, the patient was disease-free for 18 months. The clinical course and surgical therapy till 2004 was summarized by our surgical colleagues and published in this
journal in 2005 [4]. Recurrence of hepatic metastases was diagnosed in September 2005 and we now describe the clinical course and therapy over another 7 years. Following the diagnosis of recurrent hepatic metastases, another surgical resection combined with radiofrequency ablation of liver metastases was performed resulting in resection or ablation of all visible metastases. Despite of this aggressive surgical approach, new hepatic metastases appeared two years later. MRI of the abdomen demonstrated disseminated liver metastases with particularly high tumor load in the right hepatic lobe (Fig. 1). Given the local irresectability of the disseminated metastases and the futility of systemic chemotherapy regimens in the past, and after discussion in our multidisciplinary tumor board and with the patients consent, we decided to perform an experimental treatment using selective internal radiotherapy (SIRT). Pretherapeutic angiography of the hepatic arteries documented a strong perfusion and vascularization of the metastases without aberrant vessels (Fig. 2). To rule out relevant hepatopulmonary shunts albumin aggregated 99mTechnetium (99mTechnetium-MAA) was applied (Fig. 3A). After exclusion of aberrant vessels and relevant shunt fractions, SIRT was performed with 2.5 gigabequerel (GBq) 90Yttrium-microspheres which resulted in an excellent imaging of the 90Yttrium-signal in the liver via Bremsstrahlung-scan (Fig. 3B). The post-interventional follow up was free of complications. The right hepatic lobe became atrophic over time and the metastatic lesions vanished. In parallel, hypertrophy of parts of the left hepatic lobe, in particular of the caudate lobe occurred which partly compensated the hepatic function of the atrophic right hepatic lobe. Nevertheless the hepatic function decreased with an impaired INR of approx. 1.6 but has remained stable for the past four years. The clinical condition of the patient has been good for the four years following SIRT and ten years after first diagnosis. However, 8 years after first surgery and 2 years after SIRT, two paraaortal lymph node metastases with slow growth pattern were
Fig. 1. Ferucarbotran (Resovist)-enhanced magnetic resonance imaging. The upper panels demonstrate native coronar T1-imagings, the lower panels show transversal Ferucarbotran (Resovist)-enhanced T1-images. Altogether, the MR-images show disseminated hepatic lesions in 2005, 3 years after initial surgery and 24 months after the last resection of liver metastases. The main tumor burden (>90%) is located in the right hepatic lobe with hypervascularized reference metastases in segment 4a (e.g. 2.3 2 cm ¼ white star) and diffuse lesions in segments 6 (e.g. 2.6 1.9 cm ¼ white ring) and 7 (e.g. 0.8 0.8 cm ¼ white arrows).
S. Krug et al. / Pancreatology 12 (2012) 423e427
425
Fig. 2. Angiography displaying the hepatic lesions. Angiograhic imaging of the celiac trunk with typical arterial hepatic perfusion and multiple hypervascularized hepatic metastases in different time phases (early arterial, arterial and venous phase from left to right). An optimal arterial vascularization of the disseminated metastases with a predominant location within the right hepatic lobe is depicted. Note the absence of aberrant hepatopulmonary shunts or flow into gastrointestinal arteries.
detected and surgically removed without macroscopic or microscopic residues. Currently, two years after the last operation, there is no evidence for recurrence of hepatic or extrahepatic metastases (Fig. 4). 3. Discussion Solid pseudopapillary neoplasms of the pancreas (SPN) are very rare with an estimated incidence of less than 1/100,000 inhabitants per year, which are usually benign and affect the young adults [5e7]. If diagnosed early almost all patients benefit from an adequate radical surgery and will be cured. However, the nonspecific abdominal symptoms are mostly vague which frequently delays the correct diagnosis and may lead to tumor progression resulting in locally advanced disease. The cellular origin of the tumor still remains to be elucidated. In the literature, migrated
genital ridge cells, cells of neuroendocrine lineages as well as pancreatic multipotential precursor or stem cells have been proposed as tumor-initiating cells of SPN [8,9]. The pathological and molecular features underlying a benign or malignant course of SPN are not well understood. SPN occurring in older and male patients have been reported to be more aggressive [10]. Macroscopic features suggesting a malignant SPN phenotype include large tumor size (>6 cm), localization in the pancreatic tail and a disrupted capsule [11]. Perineural-, vessel- or deep pancreatic invasion indicates malignancy on histopathological evaluation [12]. SPN can be characterized by a wide range of immunohistochemical markers. This is in accordance with the hypothesis that SPN originate from pluripotent stem cells (immunomarkers see Table 1) [13]. Most commonly used markers for SPN that were also shown to be positive in our patient include NSE, vimentin, progesterone receptor and a1-antitrypsin. The primary tumor in
Fig. 3. 99mTechnetium-MAA-scan and Bremsstrahlung-scan. A. Prior to SIRT, 99mTechnetium-MAA-scan was performed to document the absence of relevant hepatopulmonary shunts with a calculated shunt fraction <5% and that the main signal uptake occurs in the liver. The planar whole-body images in anterior and posterior position were accomplished with a g-Camera. B. The planar Bremsstrahlung-scan was performed 24 h after 90Yttrium therapy in anterior and posterior images. Whereas the outer limits of the liver are not definable there is a diffuse enhancement in the liver compartment without any relevant extra-hepatic accumulations.
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S. Krug et al. / Pancreatology 12 (2012) 423e427
Fig. 4. CT and MRI scans 3-years after SIRT. A: the post-SIRT abdominal CT in coronar (left) and transversal (right) plain showing the hypertrophied left hepatic lobe, in particular the caudate lobe (white closed arrow) in comparison to the atrophied right lobe (white open arrow). The hypervascularized atrophic right lobe contains cystic lesions as residues after SIRT. No tumorous lesions are detectable. B: corresponding post-SIRT MRI scans in a coronar plain (left, T2-weighted) and a plain transversal (right, contrast-enhanced T1weighted). Vena cava ¼ dotted closed arrow; Portal vein allograft ¼ dotted open arrow.
our patient displayed a low Ki-67 index of <1%. Since the existing literature suggests that the malignant potential of SPNs correlates to the Ki-67 labeling index, this could serve as an indication for a more favorable tumor biology [14e16]. However, the clinical course in our patient, with a rapid progress of metastases and reappearance of metastases after surgical resection argues against this suggestion. On a molecular level, the knowledge on genetic alterations and oncogenic pathways involved in SPN development and progression is still rudimentary. A contribution of the Wnt-pathway during carcinogenesis in the SPN was demonstrated, with primary SPN tissues expressing nuclear b-catenin and lacking membranous E-cadherin [17,18]. The majority of these cases revealed mutations in the exon-3 of b-catenin as the key factor for nuclear accumulation, leading to diminished degradation, nuclear translocation and an increased transcriptional activity [19e23]. In contrast, the EGFR pathway including the downstream GTPase K-ras was not altered in any of the reported case series [7,19,24] and in whole genome sequencing of SPN [23]. Indeed, K-ras mutations have been suggested to help distinguishing pancreatic adenocarcinomas from SPN. To our knowledge, this is the first report of an SPN demonstrating a K-ras mutation in codon 12 that might be relevant for its malignant behavior. Besides surgical resection, multimodal treatment options for liver metastases in SPN patients include locally ablative
interventions such alcohol injection, antiangiogenic approaches such as transarterial chemoembolization as well as radiation therapy and liver transplantation [25]. The radiosensitivity of SPN was first suggested in 1985 and was proposed to be suitable for unresectable SPN [26,27]. An alternative approach in this context is selective internal radiotherapy (SIRT), the combination of interstitial radiotherapy and arterial microembolization. To our knowledge, this is the first report of the feasibility of SIRT in SPN liver metastases leading to a long-term remission. The technical feasibility of SIRT has been shown in primary and secondary liver cancers, in particular in hepatocellular carcinomas as well as liver metastases of colorectal cancer and neuroendocrine tumors [28,29]. SIRT represents a promising strategy in strongly vascularized liver metastases, given the fact that liver tumors derive nearly 100% of their blood flow from the hepatic arterial system [30]. The microspheres, consisting of resin- or glass-particles, are biocompatible but not biodegradable and therefore permanently remain in the terminal arterioles of the tumor vasculature [31]. 90Yttrium is a pure b-emitter and has a half-time of a few days. With a low median radiation range of 2.5 mm, 90Yttrium is able to produce high local exposures up to 3000 Gy [29,32]. The implementation of SIRT requires a high level of expertise in a high-volume center including adequate pretherapeutic testing and post-interventional follow-up of the patients. Contraindications for SIRT include end-stage liver disease (Child-Pugh state late BeC), ascites, bile duct obstruction,
S. Krug et al. / Pancreatology 12 (2012) 423e427
prior regional external beam radiotherapy, a hepato-pulmonary shunt volume >20% and a flow of 90Yttrium-microspheres into gastrointestinal arteries [29,31]. Evaluation of the vascular anatomy and exclusion of aberrant arterial vessels by an angiography before starting SIRT therefore is mandatory. In the presence of flow to gastrointestinal arteries, coiling of the involved vessels is an option [33]. In our case report the young female patient showed only intrahepatic lesions with well-preserved liver function and thereby was a good candidate for SIRT. A normal vascular anatomy and the hepato-pulmonary shunt volume <5% (Fig. 3) observed during pretherapeutic evaluation were optimal prerequisites. In summary, SIRT has to be considered as a feasible and safe treatment in non-resectable liver metastases of solid pseudopapillary pancreas neoplasms. Due to a lack of evidence for other nonsurgical approaches including chemotherapy, arterial chemoembolization and radiofrequency ablation, SIRT represents a promising alternative for a prolonged control of intrahepatic tumor load and improvement of the patient’s prognosis. References [1] Dufort S, Richard MJ, de Fraipont F. Pyrosequencing method to detect KRAS mutation in formalin-fixed and paraffin-embedded tumor tissues. Anal Biochem Aug 2009;391(2):166e8. [2] Do H, Krypuy M, Mitchell PL, Fox SB, Dobrovic A. High resolution melting analysis for rapid and sensitive EGFR and KRAS mutation detection in formalin fixed paraffin embedded biopsies. BMC Cancer 2008;8:142. [3] Krypuy M, Newnham GM, Thomas DM, Conron M, Dobrovic A. High resolution melting analysis for the rapid and sensitive detection of mutations in clinical samples: KRAS codon 12 and 13 mutations in non-small cell lung cancer. BMC Cancer 2006;6:295. [4] Hassan I, Celik I, Nies C, et al. Successful treatment of solid-pseudopapillary tumor of the pancreas with multiple liver metastases. Pancreatology 2005;5(2e3):289e94. [5] Rebhandl W, Felberbauer FX, Puig S, et al. Solid-pseudopapillary tumor of the pancreas (Frantz tumor) in children: report of four cases and review of the literature. J Surg Oncol Apr 2001;76(4):289e96. [6] Matos JM, Grützmann R, Agaram NP, et al. Solid pseudopapillary neoplasms of the pancreas: a multi-institutional study of 21 patients. J Surg Res Nov 2009; 157(1):e137e42. [7] Munding J, Sunitsch S, Belyaev O, Liffers ST, Uhl W, Tannapfel A. Solid pseudopapillary tumors of the pancreas: a case series, comparison of histopathological and clinical data. Z Gastroenterol Oct 2011;49(10):1417e22. [8] Salvia R, Bassi C, Festa L, et al. Clinical and biological behavior of pancreatic solid pseudopapillary tumors: report on 31 consecutive patients. J Surg Oncol Mar 2007;95(4):304e10. [9] Cavard C, Audebourg A, Letourneur F, et al. Gene expression profiling provides insights into the pathways involved in solid pseudopapillary neoplasm of the pancreas. J Pathol Jun 2009;218(2):201e9. [10] Mao C, Guvendi M, Domenico DR, Kim K, Thomford NR, Howard JM. Papillary cystic and solid tumors of the pancreas: a pancreatic embryonic tumor? Studies of three cases and cumulative review of the world’s literature. Surgery Nov 1995;118(5):821e8. [11] Yin Q, Wang M, Wang C, et al. Differentiation between benign and malignant solid pseudopapillary tumor of the pancreas by MDCT. Eur J Radiol Apr 2012. [12] Lee SE, Jang JY, Hwang DW, Park KW, Kim SW. Clinical features and outcome of solid pseudopapillary neoplasm: differences between adults and children. Arch Surg Dec 2008;143(12):1218e21.
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[13] Santini D, Poli F, Lega S. Solid-papillary tumors of the pancreas: histopathology. JOP 2006;7(1):131e6. [14] Yang B, Tan YS, Ji Y, Liu T, Zeng HY. Study on clinicopathologic features and metastasizing potential of solid pseudopapillary tumor of pancreas. Zhonghua Bing Li Xue Za Zhi Jan 2010;39(1):25e30. [15] Brázdil J, Hermanová M, Kren L, et al. Solid pseudopapillary tumor of the pancreas: 5 case reports. Rozhl Chir Feb 2004;83(2):73e8. [16] Kang CM, Kim HK, Kim H, et al. Expression of Wnt target genes in solid pseudopapillary tumor of the pancreas: a pilot study. Pancreas Mar 2009; 38(2):e53e9. [17] Huang SC, Ng KF, Yeh TS, Chang HC, Su CY, Chen TC. Clinicopathological analysis of b-catenin and axin-1 in solid pseudopapillary neoplasms of the pancreas. Ann Surg Oncol Jul 2011. [18] Nguyen NQ, Johns AL, Gill AJ, et al. Clinical and immunohistochemical features of 34 solid pseudopapillary tumors of the pancreas. J Gastroenterol Hepatol Feb 2011;26(2):267e74. [19] Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol Apr 2002; 160(4):1361e9. [20] Tanaka Y, Kato K, Notohara K, et al. Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm. Cancer Res Dec 2001;61(23):8401e4. [21] Heiser PW, Cano DA, Landsman L, et al. Stabilization of beta-catenin induces pancreas tumor formation. Gastroenterology Oct 2008;135(4):1288e300. [22] Tiemann K, Heitling U, Kosmahl M, Klöppel G. Solid pseudopapillary neoplasms of the pancreas show an interruption of the Wnt-signaling pathway and express gene products of 11q. Mod Pathol Sep 2007;20(9): 955e60. [23] Wu J, Jiao Y, Dal Molin M, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitindependent pathways. Proc Natl Acad Sci U S A Dec 2011;108(52):21188e93. [24] Yeh TS, Jan YY, Chiu CT, et al. Characterisation of oestrogen receptor, progesterone receptor, trefoil factor 1, and epidermal growth factor and its receptor in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma. Gut Nov 2002;51(5):712e6. [25] Sumida W, Kaneko K, Tainaka T, Ono Y, Kiuchi T, Ando H. Liver transplantation for multiple liver metastases from solid pseudopapillary tumor of the pancreas. J Pediatr Surg Dec 2007;42(12):e27e31. [26] Fried P, Cooper J, Balthazar E, Fazzini E, Newall J. A role for radiotherapy in the treatment of solid and papillary neoplasms of the pancreas. Cancer Dec 1985; 56(12):2783e5. [27] Papavramidis T, Papavramidis S. Solid pseudopapillary tumors of the pancreas: review of 718 patients reported in English literature. J Am Coll Surg Jun 2005;200(6):965e72. [28] Prompers L, Bucerius J, Brans B, Temur Y, Berger L, Mottaghy FM. Selective internal radiation therapy (SIRT) in primary or secondary liver cancer. Methods Nov 2011;55(3):253e7. [29] Gulec SA, Mesoloras G, Dezarn WA, McNeillie P, Kennedy AS. Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: the tumor selectivity of the treatment as a function of tumor to liver flow ratio. J Transl Med 2007;5:15. [30] Kennedy AS, Coldwell D, Nutting C, et al. Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience. Int J Radiat Oncol Biol Phys Jun 2006;65(2):412e25. [31] Wang SC, Bester L, Burnes JP, et al. Clinical care and technical recommendations for 90yttrium microsphere treatment of liver cancer. J Med Imaging Radiat Oncol Jun 2010;54(3):178e87. [32] Campbell AM, Bailey IH, Burton MA. Tumour dosimetry in human liver following hepatic yttrium-90 microsphere therapy. Phys Med Biol Feb 2001; 46(2):487e98. [33] Hoffmann RT, Jakobs TF, Tatsch K, Reiser MF. Selective internal radiotherapy for advanced liver tumors and metastases. Dtsch Med Wochenschr Oct 2008; 133(41):2099e102.
Contents lists available at SciVerse ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Case report
Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN) S. Krug a, D.K. Bartsch b, M. Schober a, D. Librizzi c, A. Pfestroff c, M. Burbelko d, R. Moll e, P. Michl a,1, T.M. Gress a, *,1 a
Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany Department of Surgery, Philipps-University Marburg, Germany Department of Nuclear Medicine, Philipps-University Marburg, Germany d Department of Radiology, Philipps-University Marburg, Germany e Department of Pathology, Philipps-University Marburg, Germany b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 June 2012 Received in revised form 14 July 2012 Accepted 16 July 2012
Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1e5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (w90%) and normally present with unspecific symptoms. We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence. This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases. Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: SPN SIRT K-ras
1. Methodology We retrospectively analyzed a patient with SPN treated and in follow-up at our institution since 2002. Tumor tissue was analyzed immunohistochemically concerning expression of NSE, Vimentin, progesterone receptor, b-catenin, p53, Ki-67, a1-antrypsin, a1-antichymotrypsin, estrogene receptor, CD 117 and CD 10. Analyses were performed according to a standardized protocol using Leica-Bond-Max-Autostainer and the antibodies in the following dilutions: NSE: Dako 1:500; Vimentin: Dako 1:400; progesterone receptor: Leica/menarini 1:100; b-catenin: BD Transduction 1:50; p53: Leica/Menarini 1:50; Ki-67: Dako 1:100; a1-antitrypsin: Dako 1:50.000; a1-antichymotrypsin Dako 1:40.000; estrogene receptor: Leica/Menarini 1:100; CD 117: Dako 1:150; CD 10: Leica/ Menarini 1:20. * Corresponding author. Tel.: þ49 6421 5866460; fax: þ49 6421 5868922. E-mail address: [email protected] (T.M. Gress). 1 Shared last authorship.
High resolution melting analysis and pyrosequenzing detecting somatic mutations in exon 2 in codons 12 and 13 of the K-ras gene were done as previously described [1e3]. 2. Case report A 16-years-old Asian woman was referred to our hospital in 2002 for second opinion who had been diagnosed earlier this year with a metastatic solid pseudopapillary neoplasm of the pancreas (SPN) in Thailand. An initial surgical exploration performed in Bangkok in May 2002 had shown local irresectability. Furthermore, sequential palliative courses of chemotherapy consisting of gemcitabine followed by combination therapies with ifosfamide, etoposide and cisplatin had failed to show clinical response. Subsequently, the patient presented to our hospital for reevaluation. Since an aggressive surgical treatment was considered as the only promising strategy in this scenario, the patient was offered a second surgical exploration aiming at radical resection. In two sequential surgical interventions a pylorus-preserving partial duodenopancreatectomy
1424-3903/$ e see front matter Copyright Ó 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pan.2012.07.014
424
S. Krug et al. / Pancreatology 12 (2012) 423e427
Table 1 Histological and molecular findings of the SPN and the liver metastases in the reported patient in comparison to the literature [7,32,33]. Immunohistochemical examinations
Literature
Our patient
NSE Vimentin Progesterone receptor b-catenin
þ þ >80% positive þ
p53
>80% positive
MIB-1/Ki-67 a1-Antitrypsin a1-Antichymotrypsin Estrogene receptor CD 117 (c-kit) CD 10 EGFR K-ras
<1% þ <80% positive e 50% >80% positive Wt Wt
þ þ 10e20% positive >80% positive, nuclear and cell membrane very weakly heterogeneously positive (w30%) <1% þ heterogeneously w50% positive e e >80% positive e Codon 12 mutation
þ ¼ positive 80e100%; ¼ negative; wt ¼ wild-type.
with resection and allografting of the portal vein and right hemicolectomy as well as resection of 12 liver metastases were performed. The 20 12 10 cm measuring primary bulk and the multiple hepatic metastases showed typical histological features of SPN with Ki-67 <1% (Table 1). The histological assessment of the surgical specimens also revealed a hemangiosis carcinomatosa as well as mesenterial metastases, but initially no lymphatic involvement in sections of approximately 30 lymph nodes. High resolution melting analysis followed by pyrosequencing for K-ras mutations was done as previously described [1e3] and detected activating mutations in codon 12 (GGT > GAT). Following surgical resection, the patient was disease-free for 18 months. The clinical course and surgical therapy till 2004 was summarized by our surgical colleagues and published in this
journal in 2005 [4]. Recurrence of hepatic metastases was diagnosed in September 2005 and we now describe the clinical course and therapy over another 7 years. Following the diagnosis of recurrent hepatic metastases, another surgical resection combined with radiofrequency ablation of liver metastases was performed resulting in resection or ablation of all visible metastases. Despite of this aggressive surgical approach, new hepatic metastases appeared two years later. MRI of the abdomen demonstrated disseminated liver metastases with particularly high tumor load in the right hepatic lobe (Fig. 1). Given the local irresectability of the disseminated metastases and the futility of systemic chemotherapy regimens in the past, and after discussion in our multidisciplinary tumor board and with the patients consent, we decided to perform an experimental treatment using selective internal radiotherapy (SIRT). Pretherapeutic angiography of the hepatic arteries documented a strong perfusion and vascularization of the metastases without aberrant vessels (Fig. 2). To rule out relevant hepatopulmonary shunts albumin aggregated 99mTechnetium (99mTechnetium-MAA) was applied (Fig. 3A). After exclusion of aberrant vessels and relevant shunt fractions, SIRT was performed with 2.5 gigabequerel (GBq) 90Yttrium-microspheres which resulted in an excellent imaging of the 90Yttrium-signal in the liver via Bremsstrahlung-scan (Fig. 3B). The post-interventional follow up was free of complications. The right hepatic lobe became atrophic over time and the metastatic lesions vanished. In parallel, hypertrophy of parts of the left hepatic lobe, in particular of the caudate lobe occurred which partly compensated the hepatic function of the atrophic right hepatic lobe. Nevertheless the hepatic function decreased with an impaired INR of approx. 1.6 but has remained stable for the past four years. The clinical condition of the patient has been good for the four years following SIRT and ten years after first diagnosis. However, 8 years after first surgery and 2 years after SIRT, two paraaortal lymph node metastases with slow growth pattern were
Fig. 1. Ferucarbotran (Resovist)-enhanced magnetic resonance imaging. The upper panels demonstrate native coronar T1-imagings, the lower panels show transversal Ferucarbotran (Resovist)-enhanced T1-images. Altogether, the MR-images show disseminated hepatic lesions in 2005, 3 years after initial surgery and 24 months after the last resection of liver metastases. The main tumor burden (>90%) is located in the right hepatic lobe with hypervascularized reference metastases in segment 4a (e.g. 2.3 2 cm ¼ white star) and diffuse lesions in segments 6 (e.g. 2.6 1.9 cm ¼ white ring) and 7 (e.g. 0.8 0.8 cm ¼ white arrows).
S. Krug et al. / Pancreatology 12 (2012) 423e427
425
Fig. 2. Angiography displaying the hepatic lesions. Angiograhic imaging of the celiac trunk with typical arterial hepatic perfusion and multiple hypervascularized hepatic metastases in different time phases (early arterial, arterial and venous phase from left to right). An optimal arterial vascularization of the disseminated metastases with a predominant location within the right hepatic lobe is depicted. Note the absence of aberrant hepatopulmonary shunts or flow into gastrointestinal arteries.
detected and surgically removed without macroscopic or microscopic residues. Currently, two years after the last operation, there is no evidence for recurrence of hepatic or extrahepatic metastases (Fig. 4). 3. Discussion Solid pseudopapillary neoplasms of the pancreas (SPN) are very rare with an estimated incidence of less than 1/100,000 inhabitants per year, which are usually benign and affect the young adults [5e7]. If diagnosed early almost all patients benefit from an adequate radical surgery and will be cured. However, the nonspecific abdominal symptoms are mostly vague which frequently delays the correct diagnosis and may lead to tumor progression resulting in locally advanced disease. The cellular origin of the tumor still remains to be elucidated. In the literature, migrated
genital ridge cells, cells of neuroendocrine lineages as well as pancreatic multipotential precursor or stem cells have been proposed as tumor-initiating cells of SPN [8,9]. The pathological and molecular features underlying a benign or malignant course of SPN are not well understood. SPN occurring in older and male patients have been reported to be more aggressive [10]. Macroscopic features suggesting a malignant SPN phenotype include large tumor size (>6 cm), localization in the pancreatic tail and a disrupted capsule [11]. Perineural-, vessel- or deep pancreatic invasion indicates malignancy on histopathological evaluation [12]. SPN can be characterized by a wide range of immunohistochemical markers. This is in accordance with the hypothesis that SPN originate from pluripotent stem cells (immunomarkers see Table 1) [13]. Most commonly used markers for SPN that were also shown to be positive in our patient include NSE, vimentin, progesterone receptor and a1-antitrypsin. The primary tumor in
Fig. 3. 99mTechnetium-MAA-scan and Bremsstrahlung-scan. A. Prior to SIRT, 99mTechnetium-MAA-scan was performed to document the absence of relevant hepatopulmonary shunts with a calculated shunt fraction <5% and that the main signal uptake occurs in the liver. The planar whole-body images in anterior and posterior position were accomplished with a g-Camera. B. The planar Bremsstrahlung-scan was performed 24 h after 90Yttrium therapy in anterior and posterior images. Whereas the outer limits of the liver are not definable there is a diffuse enhancement in the liver compartment without any relevant extra-hepatic accumulations.
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Fig. 4. CT and MRI scans 3-years after SIRT. A: the post-SIRT abdominal CT in coronar (left) and transversal (right) plain showing the hypertrophied left hepatic lobe, in particular the caudate lobe (white closed arrow) in comparison to the atrophied right lobe (white open arrow). The hypervascularized atrophic right lobe contains cystic lesions as residues after SIRT. No tumorous lesions are detectable. B: corresponding post-SIRT MRI scans in a coronar plain (left, T2-weighted) and a plain transversal (right, contrast-enhanced T1weighted). Vena cava ¼ dotted closed arrow; Portal vein allograft ¼ dotted open arrow.
our patient displayed a low Ki-67 index of <1%. Since the existing literature suggests that the malignant potential of SPNs correlates to the Ki-67 labeling index, this could serve as an indication for a more favorable tumor biology [14e16]. However, the clinical course in our patient, with a rapid progress of metastases and reappearance of metastases after surgical resection argues against this suggestion. On a molecular level, the knowledge on genetic alterations and oncogenic pathways involved in SPN development and progression is still rudimentary. A contribution of the Wnt-pathway during carcinogenesis in the SPN was demonstrated, with primary SPN tissues expressing nuclear b-catenin and lacking membranous E-cadherin [17,18]. The majority of these cases revealed mutations in the exon-3 of b-catenin as the key factor for nuclear accumulation, leading to diminished degradation, nuclear translocation and an increased transcriptional activity [19e23]. In contrast, the EGFR pathway including the downstream GTPase K-ras was not altered in any of the reported case series [7,19,24] and in whole genome sequencing of SPN [23]. Indeed, K-ras mutations have been suggested to help distinguishing pancreatic adenocarcinomas from SPN. To our knowledge, this is the first report of an SPN demonstrating a K-ras mutation in codon 12 that might be relevant for its malignant behavior. Besides surgical resection, multimodal treatment options for liver metastases in SPN patients include locally ablative
interventions such alcohol injection, antiangiogenic approaches such as transarterial chemoembolization as well as radiation therapy and liver transplantation [25]. The radiosensitivity of SPN was first suggested in 1985 and was proposed to be suitable for unresectable SPN [26,27]. An alternative approach in this context is selective internal radiotherapy (SIRT), the combination of interstitial radiotherapy and arterial microembolization. To our knowledge, this is the first report of the feasibility of SIRT in SPN liver metastases leading to a long-term remission. The technical feasibility of SIRT has been shown in primary and secondary liver cancers, in particular in hepatocellular carcinomas as well as liver metastases of colorectal cancer and neuroendocrine tumors [28,29]. SIRT represents a promising strategy in strongly vascularized liver metastases, given the fact that liver tumors derive nearly 100% of their blood flow from the hepatic arterial system [30]. The microspheres, consisting of resin- or glass-particles, are biocompatible but not biodegradable and therefore permanently remain in the terminal arterioles of the tumor vasculature [31]. 90Yttrium is a pure b-emitter and has a half-time of a few days. With a low median radiation range of 2.5 mm, 90Yttrium is able to produce high local exposures up to 3000 Gy [29,32]. The implementation of SIRT requires a high level of expertise in a high-volume center including adequate pretherapeutic testing and post-interventional follow-up of the patients. Contraindications for SIRT include end-stage liver disease (Child-Pugh state late BeC), ascites, bile duct obstruction,
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prior regional external beam radiotherapy, a hepato-pulmonary shunt volume >20% and a flow of 90Yttrium-microspheres into gastrointestinal arteries [29,31]. Evaluation of the vascular anatomy and exclusion of aberrant arterial vessels by an angiography before starting SIRT therefore is mandatory. In the presence of flow to gastrointestinal arteries, coiling of the involved vessels is an option [33]. In our case report the young female patient showed only intrahepatic lesions with well-preserved liver function and thereby was a good candidate for SIRT. A normal vascular anatomy and the hepato-pulmonary shunt volume <5% (Fig. 3) observed during pretherapeutic evaluation were optimal prerequisites. In summary, SIRT has to be considered as a feasible and safe treatment in non-resectable liver metastases of solid pseudopapillary pancreas neoplasms. Due to a lack of evidence for other nonsurgical approaches including chemotherapy, arterial chemoembolization and radiofrequency ablation, SIRT represents a promising alternative for a prolonged control of intrahepatic tumor load and improvement of the patient’s prognosis. References [1] Dufort S, Richard MJ, de Fraipont F. Pyrosequencing method to detect KRAS mutation in formalin-fixed and paraffin-embedded tumor tissues. Anal Biochem Aug 2009;391(2):166e8. [2] Do H, Krypuy M, Mitchell PL, Fox SB, Dobrovic A. High resolution melting analysis for rapid and sensitive EGFR and KRAS mutation detection in formalin fixed paraffin embedded biopsies. BMC Cancer 2008;8:142. [3] Krypuy M, Newnham GM, Thomas DM, Conron M, Dobrovic A. High resolution melting analysis for the rapid and sensitive detection of mutations in clinical samples: KRAS codon 12 and 13 mutations in non-small cell lung cancer. BMC Cancer 2006;6:295. [4] Hassan I, Celik I, Nies C, et al. Successful treatment of solid-pseudopapillary tumor of the pancreas with multiple liver metastases. Pancreatology 2005;5(2e3):289e94. [5] Rebhandl W, Felberbauer FX, Puig S, et al. Solid-pseudopapillary tumor of the pancreas (Frantz tumor) in children: report of four cases and review of the literature. J Surg Oncol Apr 2001;76(4):289e96. [6] Matos JM, Grützmann R, Agaram NP, et al. Solid pseudopapillary neoplasms of the pancreas: a multi-institutional study of 21 patients. J Surg Res Nov 2009; 157(1):e137e42. [7] Munding J, Sunitsch S, Belyaev O, Liffers ST, Uhl W, Tannapfel A. Solid pseudopapillary tumors of the pancreas: a case series, comparison of histopathological and clinical data. Z Gastroenterol Oct 2011;49(10):1417e22. [8] Salvia R, Bassi C, Festa L, et al. Clinical and biological behavior of pancreatic solid pseudopapillary tumors: report on 31 consecutive patients. J Surg Oncol Mar 2007;95(4):304e10. [9] Cavard C, Audebourg A, Letourneur F, et al. Gene expression profiling provides insights into the pathways involved in solid pseudopapillary neoplasm of the pancreas. J Pathol Jun 2009;218(2):201e9. [10] Mao C, Guvendi M, Domenico DR, Kim K, Thomford NR, Howard JM. Papillary cystic and solid tumors of the pancreas: a pancreatic embryonic tumor? Studies of three cases and cumulative review of the world’s literature. Surgery Nov 1995;118(5):821e8. [11] Yin Q, Wang M, Wang C, et al. Differentiation between benign and malignant solid pseudopapillary tumor of the pancreas by MDCT. Eur J Radiol Apr 2012. [12] Lee SE, Jang JY, Hwang DW, Park KW, Kim SW. Clinical features and outcome of solid pseudopapillary neoplasm: differences between adults and children. Arch Surg Dec 2008;143(12):1218e21.
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