J Gastrointest Canc (2012) 43 (Suppl 1):S171–S174 DOI 10.1007/s12029-011-9344-3
CASE REPORT
Concomitant Nonfunctional Pancreatic Neuroendocrine Tumor and Gastric GIST in a Patient Without Neurofibromatosis Type 1 Sven-Petter Haugvik & Bård Ingvald Røsok & Bjørn Edwin & Ivar Prydz Gladhaug & Øystein Mathisen
Published online: 15 November 2011 # Springer Science+Business Media, LLC 2011
Abbreviations CT Computed tomography GIST Gastrointestinal stromal tumor NF-1 Neurofibromatosis type 1 pNET Pancreatic neuroendocrine tumor Introduction Neuroendocrine tumors are rare neoplasms, stemming from the diffuse endocrine system and with potential of development in almost every organ, including the pancreas [17]. Pancreatic neuroendocrine tumors (pNET) are associated
S.-P. Haugvik (*) : B. I. Røsok : B. Edwin : I. P. Gladhaug : Ø. Mathisen Department of Gastrointestinal Surgery, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0027, Oslo, Norway e-mail:
[email protected]
with different genetic abnormalities in regulatory pathways of the cell cycle [5, 9, 10, 15, 19]. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract [20] and originate from the interstitial cell of Cajal [11]. They represent a heterogenous group of neoplasms, which is characterized by genetic alterations in the oncogenes KIT and PDGFRA [7, 8]. These oncogenes are used as molecular targets of selective tyrosine kinase inhibitors (e.g. imatinib) in the medical treatment of GIST [4]. GIST show a realtively high incidence in patients with neurofibromatosis type 1 (NF-1) [21], which is the most frequent inherited disease in the Western world [22]. There are, to the best of our knowledge, only three reported cases of pNET co-existing with GIST [1, 12, 16] (Table 1). Here, we present a rare case of concomitant pNET and gastric GIST in a patient without NF-1. This report seems to be unique as it includes clinical and cytogenetic findings.
B. I. Røsok e-mail:
[email protected]
Case Report
B. Edwin e-mail:
[email protected]
A 73-year-old man presented with acute hematuria and clinical signs of ureterolithiasis. Computed tomography (CT) of the abdomen incidentally revealed a tumor in the gastric wall (Fig. 1). On gastroscopy, a soft-tissue tumor in the fundus of the stomach was seen, and on biopsy, GIST was diagnosed. No related clinical symptoms and no signs of metastastic disease were present. There were no clinical signs of NF-1. He then underwent open surgical local resection of the gastric GIST at an external hospital. Intraoperatively, multiple small liver lesions were found. Also, exploration of the abdominal cavity showed an enlarged and indurated pancreatic tail. Histology of the
I. P. Gladhaug e-mail:
[email protected] Ø. Mathisen e-mail:
[email protected] B. Edwin Interventional Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway I. P. Gladhaug Institute of Clinical Medicine, University of Oslo, Oslo, Norway
S172
J Gastrointest Canc (2012) 43 (Suppl 1):S171–S174
Table 1 Overview of concomitant GIST and pNET in the literature GIST
pNET
NF-1
Reference
Small bowel Gaster Gaster
Pancreatic head gastrinoma Pancreatic head nonfunctional Pancreatic tail insulinoma
Yes No No
[16] [12] [1]
surgical specimen confirmed gastric GIST with positive cKIT (CD117). Prognosis was classified as low risk according to Miettinen et al. with a tumor diameter of 2.7 cm amd mitotic count of 2/50 high-power fields [14]. Cytogenetic analysis of the GIST by karyotyping of Gbanded chromosomes in short-term cultured cells showed monosomy 14 in 14/18 analysed metaphases corresponding ot the karyotype 45,XY,-14[14]/46,XY[4]. Surprisingly, histology of the liver metasasis showed tissue of neuroendocrine origin with positive staining for chromogranin A and synaptophysin and with grading NETG2 (Ki-67 7.5%). The patient was referred to our department for surgical treatment of what was thought to be a concomitant pNET in the pancreas tail. Indium-111-labelled octreotide scintigraphy was positive with pathological uptake in the pancreatic tail and in the liver (Fig. 2). A three-phase CT confirmed pathological findings in both pancreas and liver. Serum chromogranin A was normal before pancreatic surgery. The patient was discussed in our multidisciplinary team meeting, where a decision was made for laparoscopic resection of the primary tumor before initiation of palliative systemic chemotherapy for the remaining metastatic tissue.
Fig. 1 CT scan of gastric GIST (the arrow marks the GIST)
About 5 months after resection of the gastric GIST, a laparoscopic distal resection of the pancreas and splenectomy were performed, following surgical procedures described earlier [18]. Histology showed a focal pNET with T4N1M1(hep), according to the WHO classification of tumors of the digestive system [2], NETG2 (Ki-67 12.7%) and immunohistochemistry positive for chromogranin A and synaptophysin. Cytogenetic analysis of the pNET by karyotyping of G-banded chromosomes showed a normal karyotype.
Discussion This case report is, to the best of our knowledge, the fourth report of concomitant pNET and GIST [1, 12, 16] (Table 1). Among the other three reports, which included one patient with NF-1, none included cytogenetic data. Pagogna et al. reported the case of an 83-year-old man who presented with intestinal sub-occlusion due to compression by a tumor in the pancreatic head. Biopsy of a liver metastasis and the pancreatic tumor showed neuroendocrine tissue. Incidentally, two small nodules on the jejunum were found and resected. Histopathology showed jejunal GIST. The patient was treated with long-acting octreotide. In another report, Kövér et al. describes the case of a 51-year-old woman with pNET in the pancreatic head who initially underwent a Whipple’s procedure. In followup 5 months later, liver metastases were found. Exploratory
J Gastrointest Canc (2012) 43 (Suppl 1):S171–S174
S173
Fig. 2 Octreoscan of pNET with liver metastases (the arrows mark the primary and a liver metastasis)
laparotomy was performed, and intraoperatively, a small intramural gastric tumor was found. Histopathology showed gastric GIST. The third case was reported by Alabraba et al. and concerns a 76-year-old man who presented with symptoms of hypoglycaemia. CT revealed a focal lesion in the pancreatic tail upon which surgical enucleation was performed. Intraoperatively, a small tumor was found on the gastric wall and resected. Histopathology showed gastric GIST. There is an increased incidence of GIST in NF-1 patients, and certain mutations in the NF-1 gene seem to explain this [13]. However, it is unknown if this is also the case in patients without NF-1. A comparative genetic analysis was not performed or did not give any conclusive data in any of the above-mentioned reports. In our patient, karyotyping of G-banded chromosomes showed monosomy 14 in 14/18 analysed metaphases corresponding ot the karyotype 45,XY,-14[14]/46,XY[4] but could not show any chromosomal abberation in the pNET. Loss of chromosome 14 in GIST has already been observed by other authors and is probably an early change in the development of GIST [3, 6]. The cytogenetic analysis of the surgical specimen in this report is associated with the known limitations of karyotyping of G-banded chromosomes in short-term cultured cells. Follow-up might reveal if there are specific prognostic characteristics associtated with this rare oncological constellation. In conclusion, this report shows that nonfunctional pNET and GIST may co-exist in patients without NF-1. Karyotyping of G-banded chromosomes did not detect any correlation between the two tumor entities. There is a need
for further systematic evaluation of the geno-phenotypical relationship between low incidence neoplasms. Systematic cytogenetic analysis of larger series of pNET co-existing with GIST might lead to the identification of common genetic abberations. Acknowledgements We would like to thank Prof. Sverre Heim, M. D., Ph.D., for analysing the cytogenetic data, Prof. Tor Jacob Eide, M. D., Ph.D., for performing the histopathology of the pNET and Dr. Jan Gunnar Fjeld, M.D., for analysing the data from the indium-111labelled octreotide scintigraphy. Competing Interests The authors declare no conflict of interest.
References 1. Alabraba E et al. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1. WJSO. 2009;7:18. 2. Bosman FT, Carneiro F, Hruban RH. WHO classification of tumours of the digestive system. Lyon: IARC; 2010. 3. Breiner JA et al. Loss of 14q and 22q in gastrointestinal stromal tumors (pacemaker cell tumors). Cancer Genet Cytogenet. 2000;120(2):111. 4. Demetri GD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. NEJM. 2002;347 (7):472. 5. Furlan D et al. Different molecular profiles characterize welldifferentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroenteropancreatic tract. Clin Cancer Res. 2004;10(3):947. 6. Gunawan B et al. Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors. Hum Pathol. 2002;33(3):316. 7. Heinrich MC et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708.
S174 8. Hirota S et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577. 9. Jiao Y et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199. 10. Kim do H et al. Allelic alterations in well-differentiated neuroendocrine tumors (carcinoid tumors) identified by genomewide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors. Genes Chromosomes Cancer. 2008;47(1):84. 11. Kindblom LG et al. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152(5):1259. 12. Kover E et al. Dual tumours in the GI tract: synchronous and metachronous stromal (GIST) and epithelial/neuroendocrine neoplasms. Magy Onkol. 2004;48(4):315. 13. Maertens O et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet. 2006;15 (6):1015. 14. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466. 15. Missiaglia E et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28(2):245.
J Gastrointest Canc (2012) 43 (Suppl 1):S171–S174 16. Pagogna S, Zanini N, Tomassetti P. Neuroendocrine tumor of the pancreas and GIST: is there a correlation? J Pancreas. 2004;6:501. 17. Rindi G, Wiedenmann B. Neuroendocrine neoplasms of the gut and pancreas: new insights. Nat Rev Endocrinol 2011. doi:10.1038/ nrendo.2011.120. 18. Rosok BI et al. Single-centre experience of laparoscopic pancreatic surgery. BJS. 2010;97(6):902. 19. Tonnies H et al. Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut. 2001;48(4):536. 20. van der Zwan SM, DeMatteo RP. Gastrointestinal stromal tumor: 5 years later. Cancer. 2005;104(9):1781. 21. Wallace MR et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181. 22. Ward BA, Gutmann DH. Neurofibromatosis 1: from lab bench to clinic. Pediatr Neurol. 2005;32(4):221.
Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
