J Gastrointest Canc DOI 10.1007/s12029-016-9803-y
CASE REPORT
A Rare Case of a Gastrointestinal Stromal Tumor (GIST) Presenting as a Perforated Meckel’s Diverticulum Christopher R. Omerza 1 & Andrea Kay Bouman 1
&
Patrick P. Bulinski 1,2
# Springer Science+Business Media New York 2016
Introduction Meckel’s diverticulum (MD) is the most common congenital malformation of the gastrointestinal tract, with an estimated incidence of 1.2 to 4 % [1, 2]. Despite this high prevalence, complications are uncommon, with recent literature suggesting a lifetime complication risk of 4 to 16 %. The most frequent complication is GI hemorrhage associated with ectopic gastric tissue, especially in children. However, obstruction, intussusception, Meckel’s diverticulitis, ulceration, perforation, and neoplasm are also seen [2]. MD is an uncommon location for malignant tumors, with an incidence of 14.4 per 100 million person-years [3]. Gastrointestinal stromal tumors (GISTs) in a MD have an incidence of 1.5 per 100 million person-years [3]. Perforation of a GIST in a MD is an even more rare occurrence, with only 10 cases reported in the literature, and none originating in the USA [4–13]. Here, we describe a case of a GIST presenting as a perforated Meckel’s diverticulum.
Case Presentation A 55-year-old, previously healthy male presented to the emergency department with a 2-day history of worsening * Andrea Kay Bouman [email protected]
1
Michigan State University College of Human Medicine UP Campus, Marquette, MI, USA
2
UP Health System-Marquette, Marquette, MI, USA
abdominal pain and associated nausea and vomiting. The patient denied fever, hematochezia, and melena. Physical exam was significant only for mild abdominal distention and tenderness to palpation over the left midabdomen. Of note, the patient had a similar episode of abdominal pain 2 months previously and was clinically diagnosed with diverticulitis, which resolved with antibiotics. A CT scan was not performed at that time. The patient’s past medical and surgical history were otherwise unremarkable. At presentation, the patient’s white count was elevated at 26,000 with a 1+ left shift. CT of the abdomen and pelvis (Fig. 1) revealed a 5-cm mass in the left lower quadrant and a diffuse inflammatory process involving the small bowel. Preliminary report suggested Meckel’s diverticulitis with possible perforation. The patient underwent an exploratory laparotomy, which revealed cloudy, contaminated fluid within the peritoneal cavity as well as an inflammatory mass located at the left base of the urinary bladder, which appeared to be arising from a perforated Meckel’s diverticulum. The patient underwent segmental small bowel resection with removal of 24.5 cm of bowel, including the diverticulum, followed by primary anastomosis. The diverticulum was 3.5 cm in diameter and gave rise to a mass measuring 8.0 cm at its largest diameter. Histologic examination revealed a spindle cell predominant tumor. Staining revealed that the mass was strongly and diffusely CD117 positive, consistent with a gastrointestinal stromal tumor (GIST) (Fig. 2). The GIST was classified as AJCC 7th edition stage pT3 and low grade, with fewer than five mitoses per 50 highpower fields on hematoxylin and eosin staining (Fig. 3). SMA, S100, and desmin immunohistochemistry were negative. Several nonenlarged lymph nodes were noted throughout the patient’s abdomen on MRI and CT and were unchanged
J Gastrointest Canc
from previous imaging. No additional imaging was obtained to further investigate for secondary localizations of the tumor. Pathologic examination of the gross mass revealed tumor-free margins. No regional lymph nodes were excised for pathologic examination. Following an uncomplicated hospital course, the patient was discharged home on appropriate antibiotics, referred to oncology, and was prophylactically started on imatinib at a dose of 400 mg daily. At the time of this writing, the patient remains well and continues to follow with oncology.
Discussion Cancer of the small intestine is quite rare, comprising 0.5 % of all cancers and only 3.2 % of gastrointestinal cancers, despite the small intestine constituting 75 % of the length and 90 % of the absorptive surface area of the GI tract [14, 15]. The distribution of small bowel cancers has been evolving over the last several decades, with carcinoid tumors increasing (27.5 to 44.3 %) and adenocarcinoma decreasing (42.1 to 32.6 %) [16]. GISTs, which were first reported to the National Cancer Data Base in 2001, accounted for 7.1 % of small bowel cancers from 2001 to 2005, while lymphomas made up the remainder [16]. The distribution of cancer types in a Meckel’s diverticulum, however, differ from that of the small bowel. Carcinoid tumors make up the majority (77.3 %) of MD cancers, while adenocarcinomas (11.0 %) and lymphomas (1.2 %) are less common in the MD compared to the small bowel. GISTs and leiomyosarcomas collectively make up 10.4 % of MD cancers [3]. An underlying reason for the difference in tumor distribution between the small bowel and the MD has not been described. Interestingly, tumors in a Meckel’s diverticulum are approximately 70 times more common than ileal cancers on a Bper length of bowel at risk^ basis when the prevalence and length of MD are accounted for [3]. For this reason, Thirunavukarasu et al. suggest prophylactic resection of any
Fig. 1 Axial CT depicting the left lower quadrant mass originating from the small intestine. Note the fat stranding surrounding the mass
Fig. 2 ×40 view with CD117 immunostaining. This image shows strong, diffuse positivity for CD117 (Kit). Involvement of the muscularis propria is classic for GISTs
incidentally discovered MD during laparotomy [3]. However, Zani et al. argue that the high number needed to treat (NNT = 758) to prevent one MD-related death does not justify the complication rate (5.3 %) of prophylactic resections of incidental MD [1]. Gastrointestinal stromal tumors are mesenchymal tumors that originate from the interstitial cells of Cajal. The majority of GISTs are positive for the tyrosine kinase receptor Kit (CD117), although CD117 positivity is no longer required for diagnosis [17]. They are commonly found in the stomach (55 %) and small intestine (29 %), can also occur in the colon (2.9 %) and rectum (2.9 %), and have an average annual incidence of approximately 0.68 per 100,000 person-years [18]. Ma and colleagues report a 5 year overall survival rate of 65 % from 2001 to 2011, which is much better than previous studies suggesting a 5-year survival of 45 %. This increase in survival has been attributed to the introduction of imatinib [18].
Fig. 3 ×200 view with Hematoxylin and Eosin staining. Note the spindle cell predominance in a fascicular organization
J Gastrointest Canc
Imatinib mesylate, a tyrosine kinase inhibitor with activity against KIT, platelet-derived growth factor receptor alpha, and BCR-ABL, has revolutionized the treatment of GISTs since its introduction in 2000 [19–22]. Prior to imatinib, treatment of GISTs was limited to surgical resection, as response of GISTs to traditional chemotherapy has been estimated to be less than 10 % [20]. Although GISTs are resectable tumors, the prognosis with surgical treatment alone is unfavorable, with one study noting a 2-year recurrence rate of 40 % and a 5-year disease-specific survival rate of 54 % [23]. Imatinib has greatly improved survival and decreased recurrence, with one study noting a 98 % recurrence-free survival rate following 1 year of adjuvant imatinib compared to 83 % following resection alone [20]. Imatinib has also been shown to improve patient outcomes when used as a neoadjuvant therapy [24]. Although imatinib has made a significant improvement in the prognosis of GISTs, its effects are limited. Studies have found that 13 % of GISTs are primarily resistant to imatinib therapy [25], and up to 50 % of patients acquire secondary resistance and subsequent disease progression during imatinib treatment [26]. Early studies of other biologic therapies, including the multikinase inhibitor regorafenib, have demonstrated a positive effect in treating GISTs that have failed imatinib treatment [27]. While cancer-related perforation is a rare complication of Meckel’s diverticulum, underlying malignancy is an important consideration in the differential diagnosis. Although we believe this to be the first report of this unique presentation originating in the USA, it is not the only case reported in global literature, emphasizing its significance as a diagnostic consideration, especially in light of the therapies available to treat GISTs. In light of the relative propensity for malignancies to occur in Meckel’s diverticula compared to an equivalent length of ileum [3], we believe that additional research into malignancies in Meckel’s diverticula is warranted and may shed light on this discrepancy. However, given the overall rarity of the event, opportunities for further study are limited. Therefore, the authors suggest that documentation of future occurrences of this condition would be valuable and lend itself to further analysis. Acknowledgments The authors would like to acknowledge Dr. Larry S. Lewis, MD as the attending surgeon on this case. We would also like to acknowledge Dr. Jeffrey A Conklin, MD, the pathologist working with this case, for assistance with the acquisition of slides. Finally, Dr. Mark Trottier, PhD, for his assistance with article revision and editing.
References 1.
2. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. 16.
Compliance with Ethical Standards
17.
Informed Consent Informed consent was obtained from the individual described in this report.
18.
Conflict of Interest The authors declare that they have no competing interests.
Zani A, Eaton S, Rees CM, Pierro A. Incidentally detected Meckel diverticulum: to resect or not to resect? Ann Surg. 2008;247:276– 81. doi:10.1097/SLA.0b013e31815aaaf8. Sagar J, Kumar V, Shah DK. Meckel’s diverticulum: a systematic review. J R Soc Med. 2006;99:501–5. Thirunavukarasu P, Sathaiah M, Sukumar S, Bartels CJ, Zeh 3rd H, Lee KK, et al. Meckel’s diverticulum-a high-risk region for malignancy in the ileum. Insights from a population-based epidemiological study and implications in surgical management. Ann Surg. 2011;252:223–30. doi:10.1097/SLA.0b013e3181ef488d. López-Tomassetti Fernández EM, Hernández JR, Jorge VN. Perforated gastrointestinal stromal tumor in Meckel’s diverticulum treated laparoscopically. Asian J Endosc Surg. 2013;6:126–9. doi: 10.1111/ases.12016. Szentpáli K, Palotás A, Wolfárd A, Tiszlavicz L, Balogh A. A gastrointestinal stromal tumour presenting in a perforated Meckel’s diverticulum. Can J Surg. 2004;47:70. Hager M, Maier H, Eberwein M, Klingler P, Kolbitsch C, Tiefenthaler W, et al. Perforated Meckel’s diverticulum presenting as a gastrointestinal stromal tumor: a case report. J Gastrointest Surg. 2005;9:809–11. Dogrul AB, Kilic YA, Onurdag F, Onder S, Tirnaksiz MB, Abbasoglu O. A gastrointestinal stromal tumor in Meckel diverticulum in an 86-year-old patient. Am J Med Sci. 2010;340:156–7. doi:10.1097/MAJ.0b013e3181dfbb94. Caricato M, Mangiameli G, Miccadei F, Bulzomi G, Coppola R. A rare case of complicated Meckel’s diverticulum. Case report and images. Ann Ital Chir. 2010;81:449–51. Chou YH, Tu CC, Huang CC, Hsieh MS. A clinically-occult gastrointestinal stromal tumor in a Meckel’s diverticulum presenting as hollow organ perforation. Chang Gung Med J. 2011;34:56–61. Sozen S, Ömer T (2012) A rare case of perforated Meckel’s diverticulum presenting as a gastrointestinal stromal tumor. Arch Iran Med 15:325-327. doi: 012155/AIM.0016. Mitura K, Blicharz P, Romańczuk M. Perforated gist of Meckel’s diverticulum. Pol Przeql Chir. 2012;84:258–61. doi:10.2478/ v10035-012-0043-y. Woolf R, Blencowe N, Muhammad K, Paterson D, Pye G. A gastrointestinal stromal tumor presenting incidentally with haemorrhage and perforation associated with a Meckel’s diverticulum: a case report. J Med Case Rep. 2009;23:7423. doi:10.4076/17521947-3-7423. Goyal R, Chaudhary NK. Gastrointestinal stromal tumor of Meckel’s diverticulum causing perforation and peritonitis: a case report. Indian J Surg. 2013;75 Suppl 1:S171–3. doi:10.1007/ s12262-012-0556-y. Mulholland MW, Lillemoe KD, Doherty GM, et al. Greenfield’s Surgery: Scientific Principles and Practice. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin. 2015;65:5–29. doi:10.3322/caac.21254. Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS. Small bowel cancer in the Unites States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg. 2009;249:63–71. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–78. Ma GL, Murphy JD, Martinez ME, Sicklick JK. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev. 2015;24:298–302. doi:10.1158/1055-9965.
J Gastrointest Canc 19.
Verweij J, Casali PG, Zalcberg J. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–34. 20. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebocontrolled trial. Lancet. 2009;373:1097–104. doi:10.1016/ S0140-6736(09)60500-6. 21. Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–77. 22. Bonvalot S, Eldweny H, Péchoux CL, et al. Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol. 2006;13:1596–603. 23. Dematteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors:
24.
25.
26.
27.
recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–8. Fiore M, Palassini E, Fumagalli E, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol. 2008;35:739–45. doi:10. 1016/j.ejso.2008.11.005. Demetri G, Mehren MV, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80. Antonescu CR, Besmer P, Guo T. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182–90. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381: 295–302. doi:10.1016/S0140-6736(12)61857-1.
CASE REPORT
A Rare Case of a Gastrointestinal Stromal Tumor (GIST) Presenting as a Perforated Meckel’s Diverticulum Christopher R. Omerza 1 & Andrea Kay Bouman 1
&
Patrick P. Bulinski 1,2
# Springer Science+Business Media New York 2016
Introduction Meckel’s diverticulum (MD) is the most common congenital malformation of the gastrointestinal tract, with an estimated incidence of 1.2 to 4 % [1, 2]. Despite this high prevalence, complications are uncommon, with recent literature suggesting a lifetime complication risk of 4 to 16 %. The most frequent complication is GI hemorrhage associated with ectopic gastric tissue, especially in children. However, obstruction, intussusception, Meckel’s diverticulitis, ulceration, perforation, and neoplasm are also seen [2]. MD is an uncommon location for malignant tumors, with an incidence of 14.4 per 100 million person-years [3]. Gastrointestinal stromal tumors (GISTs) in a MD have an incidence of 1.5 per 100 million person-years [3]. Perforation of a GIST in a MD is an even more rare occurrence, with only 10 cases reported in the literature, and none originating in the USA [4–13]. Here, we describe a case of a GIST presenting as a perforated Meckel’s diverticulum.
Case Presentation A 55-year-old, previously healthy male presented to the emergency department with a 2-day history of worsening * Andrea Kay Bouman [email protected]
1
Michigan State University College of Human Medicine UP Campus, Marquette, MI, USA
2
UP Health System-Marquette, Marquette, MI, USA
abdominal pain and associated nausea and vomiting. The patient denied fever, hematochezia, and melena. Physical exam was significant only for mild abdominal distention and tenderness to palpation over the left midabdomen. Of note, the patient had a similar episode of abdominal pain 2 months previously and was clinically diagnosed with diverticulitis, which resolved with antibiotics. A CT scan was not performed at that time. The patient’s past medical and surgical history were otherwise unremarkable. At presentation, the patient’s white count was elevated at 26,000 with a 1+ left shift. CT of the abdomen and pelvis (Fig. 1) revealed a 5-cm mass in the left lower quadrant and a diffuse inflammatory process involving the small bowel. Preliminary report suggested Meckel’s diverticulitis with possible perforation. The patient underwent an exploratory laparotomy, which revealed cloudy, contaminated fluid within the peritoneal cavity as well as an inflammatory mass located at the left base of the urinary bladder, which appeared to be arising from a perforated Meckel’s diverticulum. The patient underwent segmental small bowel resection with removal of 24.5 cm of bowel, including the diverticulum, followed by primary anastomosis. The diverticulum was 3.5 cm in diameter and gave rise to a mass measuring 8.0 cm at its largest diameter. Histologic examination revealed a spindle cell predominant tumor. Staining revealed that the mass was strongly and diffusely CD117 positive, consistent with a gastrointestinal stromal tumor (GIST) (Fig. 2). The GIST was classified as AJCC 7th edition stage pT3 and low grade, with fewer than five mitoses per 50 highpower fields on hematoxylin and eosin staining (Fig. 3). SMA, S100, and desmin immunohistochemistry were negative. Several nonenlarged lymph nodes were noted throughout the patient’s abdomen on MRI and CT and were unchanged
J Gastrointest Canc
from previous imaging. No additional imaging was obtained to further investigate for secondary localizations of the tumor. Pathologic examination of the gross mass revealed tumor-free margins. No regional lymph nodes were excised for pathologic examination. Following an uncomplicated hospital course, the patient was discharged home on appropriate antibiotics, referred to oncology, and was prophylactically started on imatinib at a dose of 400 mg daily. At the time of this writing, the patient remains well and continues to follow with oncology.
Discussion Cancer of the small intestine is quite rare, comprising 0.5 % of all cancers and only 3.2 % of gastrointestinal cancers, despite the small intestine constituting 75 % of the length and 90 % of the absorptive surface area of the GI tract [14, 15]. The distribution of small bowel cancers has been evolving over the last several decades, with carcinoid tumors increasing (27.5 to 44.3 %) and adenocarcinoma decreasing (42.1 to 32.6 %) [16]. GISTs, which were first reported to the National Cancer Data Base in 2001, accounted for 7.1 % of small bowel cancers from 2001 to 2005, while lymphomas made up the remainder [16]. The distribution of cancer types in a Meckel’s diverticulum, however, differ from that of the small bowel. Carcinoid tumors make up the majority (77.3 %) of MD cancers, while adenocarcinomas (11.0 %) and lymphomas (1.2 %) are less common in the MD compared to the small bowel. GISTs and leiomyosarcomas collectively make up 10.4 % of MD cancers [3]. An underlying reason for the difference in tumor distribution between the small bowel and the MD has not been described. Interestingly, tumors in a Meckel’s diverticulum are approximately 70 times more common than ileal cancers on a Bper length of bowel at risk^ basis when the prevalence and length of MD are accounted for [3]. For this reason, Thirunavukarasu et al. suggest prophylactic resection of any
Fig. 1 Axial CT depicting the left lower quadrant mass originating from the small intestine. Note the fat stranding surrounding the mass
Fig. 2 ×40 view with CD117 immunostaining. This image shows strong, diffuse positivity for CD117 (Kit). Involvement of the muscularis propria is classic for GISTs
incidentally discovered MD during laparotomy [3]. However, Zani et al. argue that the high number needed to treat (NNT = 758) to prevent one MD-related death does not justify the complication rate (5.3 %) of prophylactic resections of incidental MD [1]. Gastrointestinal stromal tumors are mesenchymal tumors that originate from the interstitial cells of Cajal. The majority of GISTs are positive for the tyrosine kinase receptor Kit (CD117), although CD117 positivity is no longer required for diagnosis [17]. They are commonly found in the stomach (55 %) and small intestine (29 %), can also occur in the colon (2.9 %) and rectum (2.9 %), and have an average annual incidence of approximately 0.68 per 100,000 person-years [18]. Ma and colleagues report a 5 year overall survival rate of 65 % from 2001 to 2011, which is much better than previous studies suggesting a 5-year survival of 45 %. This increase in survival has been attributed to the introduction of imatinib [18].
Fig. 3 ×200 view with Hematoxylin and Eosin staining. Note the spindle cell predominance in a fascicular organization
J Gastrointest Canc
Imatinib mesylate, a tyrosine kinase inhibitor with activity against KIT, platelet-derived growth factor receptor alpha, and BCR-ABL, has revolutionized the treatment of GISTs since its introduction in 2000 [19–22]. Prior to imatinib, treatment of GISTs was limited to surgical resection, as response of GISTs to traditional chemotherapy has been estimated to be less than 10 % [20]. Although GISTs are resectable tumors, the prognosis with surgical treatment alone is unfavorable, with one study noting a 2-year recurrence rate of 40 % and a 5-year disease-specific survival rate of 54 % [23]. Imatinib has greatly improved survival and decreased recurrence, with one study noting a 98 % recurrence-free survival rate following 1 year of adjuvant imatinib compared to 83 % following resection alone [20]. Imatinib has also been shown to improve patient outcomes when used as a neoadjuvant therapy [24]. Although imatinib has made a significant improvement in the prognosis of GISTs, its effects are limited. Studies have found that 13 % of GISTs are primarily resistant to imatinib therapy [25], and up to 50 % of patients acquire secondary resistance and subsequent disease progression during imatinib treatment [26]. Early studies of other biologic therapies, including the multikinase inhibitor regorafenib, have demonstrated a positive effect in treating GISTs that have failed imatinib treatment [27]. While cancer-related perforation is a rare complication of Meckel’s diverticulum, underlying malignancy is an important consideration in the differential diagnosis. Although we believe this to be the first report of this unique presentation originating in the USA, it is not the only case reported in global literature, emphasizing its significance as a diagnostic consideration, especially in light of the therapies available to treat GISTs. In light of the relative propensity for malignancies to occur in Meckel’s diverticula compared to an equivalent length of ileum [3], we believe that additional research into malignancies in Meckel’s diverticula is warranted and may shed light on this discrepancy. However, given the overall rarity of the event, opportunities for further study are limited. Therefore, the authors suggest that documentation of future occurrences of this condition would be valuable and lend itself to further analysis. Acknowledgments The authors would like to acknowledge Dr. Larry S. Lewis, MD as the attending surgeon on this case. We would also like to acknowledge Dr. Jeffrey A Conklin, MD, the pathologist working with this case, for assistance with the acquisition of slides. Finally, Dr. Mark Trottier, PhD, for his assistance with article revision and editing.
References 1.
2. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. 16.
Compliance with Ethical Standards
17.
Informed Consent Informed consent was obtained from the individual described in this report.
18.
Conflict of Interest The authors declare that they have no competing interests.
Zani A, Eaton S, Rees CM, Pierro A. Incidentally detected Meckel diverticulum: to resect or not to resect? Ann Surg. 2008;247:276– 81. doi:10.1097/SLA.0b013e31815aaaf8. Sagar J, Kumar V, Shah DK. Meckel’s diverticulum: a systematic review. J R Soc Med. 2006;99:501–5. Thirunavukarasu P, Sathaiah M, Sukumar S, Bartels CJ, Zeh 3rd H, Lee KK, et al. Meckel’s diverticulum-a high-risk region for malignancy in the ileum. Insights from a population-based epidemiological study and implications in surgical management. Ann Surg. 2011;252:223–30. doi:10.1097/SLA.0b013e3181ef488d. López-Tomassetti Fernández EM, Hernández JR, Jorge VN. Perforated gastrointestinal stromal tumor in Meckel’s diverticulum treated laparoscopically. Asian J Endosc Surg. 2013;6:126–9. doi: 10.1111/ases.12016. Szentpáli K, Palotás A, Wolfárd A, Tiszlavicz L, Balogh A. A gastrointestinal stromal tumour presenting in a perforated Meckel’s diverticulum. Can J Surg. 2004;47:70. Hager M, Maier H, Eberwein M, Klingler P, Kolbitsch C, Tiefenthaler W, et al. Perforated Meckel’s diverticulum presenting as a gastrointestinal stromal tumor: a case report. J Gastrointest Surg. 2005;9:809–11. Dogrul AB, Kilic YA, Onurdag F, Onder S, Tirnaksiz MB, Abbasoglu O. A gastrointestinal stromal tumor in Meckel diverticulum in an 86-year-old patient. Am J Med Sci. 2010;340:156–7. doi:10.1097/MAJ.0b013e3181dfbb94. Caricato M, Mangiameli G, Miccadei F, Bulzomi G, Coppola R. A rare case of complicated Meckel’s diverticulum. Case report and images. Ann Ital Chir. 2010;81:449–51. Chou YH, Tu CC, Huang CC, Hsieh MS. A clinically-occult gastrointestinal stromal tumor in a Meckel’s diverticulum presenting as hollow organ perforation. Chang Gung Med J. 2011;34:56–61. Sozen S, Ömer T (2012) A rare case of perforated Meckel’s diverticulum presenting as a gastrointestinal stromal tumor. Arch Iran Med 15:325-327. doi: 012155/AIM.0016. Mitura K, Blicharz P, Romańczuk M. Perforated gist of Meckel’s diverticulum. Pol Przeql Chir. 2012;84:258–61. doi:10.2478/ v10035-012-0043-y. Woolf R, Blencowe N, Muhammad K, Paterson D, Pye G. A gastrointestinal stromal tumor presenting incidentally with haemorrhage and perforation associated with a Meckel’s diverticulum: a case report. J Med Case Rep. 2009;23:7423. doi:10.4076/17521947-3-7423. Goyal R, Chaudhary NK. Gastrointestinal stromal tumor of Meckel’s diverticulum causing perforation and peritonitis: a case report. Indian J Surg. 2013;75 Suppl 1:S171–3. doi:10.1007/ s12262-012-0556-y. Mulholland MW, Lillemoe KD, Doherty GM, et al. Greenfield’s Surgery: Scientific Principles and Practice. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin. 2015;65:5–29. doi:10.3322/caac.21254. Bilimoria KY, Bentrem DJ, Wayne JD, Ko CY, Bennett CL, Talamonti MS. Small bowel cancer in the Unites States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg. 2009;249:63–71. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–78. Ma GL, Murphy JD, Martinez ME, Sicklick JK. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev. 2015;24:298–302. doi:10.1158/1055-9965.
J Gastrointest Canc 19.
Verweij J, Casali PG, Zalcberg J. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–34. 20. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebocontrolled trial. Lancet. 2009;373:1097–104. doi:10.1016/ S0140-6736(09)60500-6. 21. Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–77. 22. Bonvalot S, Eldweny H, Péchoux CL, et al. Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol. 2006;13:1596–603. 23. Dematteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors:
24.
25.
26.
27.
recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–8. Fiore M, Palassini E, Fumagalli E, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol. 2008;35:739–45. doi:10. 1016/j.ejso.2008.11.005. Demetri G, Mehren MV, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80. Antonescu CR, Besmer P, Guo T. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182–90. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381: 295–302. doi:10.1016/S0140-6736(12)61857-1.
