Published Ahead of Print on June 30, 2014 as 10.1200/JCO.2013.48.9302 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.48.9302
Case Report The patient, an 81-year-old white man, had a history of GI stromal tumor (GIST) of the small bowel that was diagnosed in December 2005. At that time he underwent small bowel resection with complete surgical removal of the tumor. Pathologic evaluation revealed a 4-cm GIST with low mitotic rate and no regional lymph node involvement. Imaging revealed no distant metastatic disease. Thus, the patient did not receive adjuvant therapy. He remained disease free until January 2012. At that time, he presented with a 3-month history of progressive abdominal pain. Computed tomography (CT) imaging revealed an 11 ⫻ 9.5 ⫻ 8 – cm right abdominal mass. CT-guided biopsy confirmed recurrent GIST. The patient began receiving imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ). After 3 months of therapy, he required hospital admission for progressive confusion and weakness with no focal neurologic deficit. The serum ammonia level at that time was 171 mol/L (normal level, ⬍ 42 mol/L; Fig 1). Repeat imaging showed progression of disease with increased tumor size to 12 ⫻ 18 ⫻ 15 cm with surrounding varices (Fig 2A, red arrow) and multiple new intra-abdominal masses that were consistent with sarcomatosis. A portosystemic shunt was also noted between the varices from the tumor and the right renal vein (Fig 2B, red arrow) and renal cortex (Fig 2C, red arrow). There was no evidence of hepatic metastases or liver dysfunction. Using the consensus report of the Working Party at the 11th World Congresses of Gastroenterology,1 our patient would be classified as having type B encephalopathy, grade 2. Imatinib mesylate was discontinued and treatment with sunitinib malate (Sutent; Pfizer, New York, NY) was initiated in addition to lactulose therapy. The patient experienced moderate improvement in his mental status with corresponding improvement in his ammonia levels, although they never reached a normal level. He required emergent admission for profound encephalopathy (type B, grade 3) 2.5 months later. This was associated with a serum ammonia level of 155 mol/L (Fig 1) and progressive abdominal disease. Evaluation for other causes of encephalopathy and hyperammonemia was unrevealing. Assessment included serum hepatic function tests, serum metabolic levels, toxin screen, basic urea cycle enzyme levels, and urine amino acid levels. Brain magnetic resonance imaging was negative, and T1 signal hyperintensity in the basal ganglia was not demonstrated. Hepatic imaging was also negative. The patient continued to be confused and disoriented despite continued lactulose treatment and discontinuation of sunitinib malate. Because of the lack of improvement in mental status and the possibility that the tumor was the cause of the hyperammonemia, the patient underwent operative tumor debulking. Findings included a large multilobulated abdominal tumor with numerous surrounding varices (Fig 3) in addition to sarcomatosis involving the lower abdomen and pelvis. There was no evidence of liver metastases. The tumor Journal of Clinical Oncology, Vol 32, 2014
180
Serum Ammonia (µmol/L)
Hyperammonemic Encephalopathy Associated With GI Stromal Tumor
D I A G N O S I S
160 140
I N
* †
O N C O L O G Y
Surgical tumor debulking ‡
120 100 80 60 40 20 0
5/3 1/2 6/7 012 6/1 /201 4/ 2 6/2 201 1/2 2 6/2 01 8/2 2 7/5 012 7/1 /201 2/ 2 7/1 201 9 2 7/2 /201 6/2 2 8/2 012 / 8/9 2012 /20 8/1 1 6 2 8/2 /201 3/ 2 8/2 201 3/2 2 9/6 012 9/1 /201 3 2 9/2 /201 0/ 2 9/2 201 7 2 10 /201 /4/ 2 10 20 /11 12 /20 12
JOURNAL OF CLINICAL ONCOLOGY
Date Fig 1.
was removed in continuity with involved colon and small bowel along with debulking of peritoneal disease. Pathologic evaluation revealed a 14-cm GIST with 11 mitoses/50 high-power fields (hpf) and greater than 90% viable tumor. Tumor cells were strongly immunoreactive with CD117 (c-kit) and CD34 antibodies. Tumor cells were negative with S-100, desmin, and smooth muscle-specific actin antibodies. Platelet-derived growth factor receptor-␣ was not tested. The serum ammonia level in the recovery room 1 hour after surgery showed remarkable normalization to 33 mol/L (Fig 1) with return to normal mental status on postoperative day 1. The patient recovered from surgery and was discharged to return home. Serum ammonia levels remained normal with no recurrent encephalopathy 8 months after surgery. Discussion We describe a patient with hyperammonemic encephalopathy that was associated with GIST. The pathophysiologic mechanism may involve tumor production of ammonia and require a tumorportosystemic shunt to reveal encephalopathy. The preoperative CT imaging revealed tumor-related varices draining into the right renal vein (Fig 2B) and renal cortex (Fig 2C), supporting the concept of a portosystemic shunt for the development of hyperammonemia with resultant encephalopathy. In addition, the serum ammonia level was looselycorrelatedwithdiseaseburdeninthispatient,whichwasevidenced by progressive hyperammonemia that was associated with disease progressiononserialimaging,andrapidresolutionaftersurgicalresection.To our knowledge, this is the first report of an ammonia-secreting GIST tumor causing hyperammonemic encephalopathy. There have been several chemotherapeutic and targeted systemic agents in cancer therapy that are implicated in hyperammonemia, notably fluorouracil and sunitinib malate.2-7 In a Japanese report of 18 patients with advanced GIST treated with sunitinib malate after failure © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on September 16, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Chiu, Zaghiyan, and Silberman
A
B Fig 3.
C
Fig 2.
of imatinib mesylate therapy, one patient developed irreversible hyperammonemia and flapping tremor.2 The authors attributed this finding to sunitinib therapy and its antiangiogenic properties. However, the report also describes the identification of a portosystemic shunt on CT imaging of the patient. Alternatively, this finding would support the possibility of serum accumulation of ammonia that may be directly produced by the GIST. In another report, two patients presented with confusion and dramatic hyperammonemia that occurred at 17 and 10 days after initiation of sunitinib malate therapy for 2
© 2014 by American Society of Clinical Oncology
metastatic GIST.3 After treatment with lactulose enemas and discontinuation of sunitinib malate, both patients experienced improvement in mental status. Serum ammonia levels improved but did not return to normal. Sunitinib malate was restarted in one patient, resulting in recurrence of confusion and hyperammonemia after 7 days of therapy. Although the serum ammonia level and mental status change correlated closely with the timing of sunitinib malate therapy, resolution of these disturbances may have been attributable to treatment with lactulose enemas rather than discontinuation of sunitinib malate. In addition, both patients had continued demonstrable disease. Thus, hyperammonemia may have been the result of progressive tumor burden and may not have been caused by the sunitinib malate therapy. Indeed, multiple myeloma cells have been postulated to induce hyperammonemia as a result of altered amino acid metabolism.8-10 This same mechanism may be present in GIST and requires further study. There have been several paraneoplastic syndromes described in association with GIST.11-17 Severe symptomatic hypoglycemia was reported in a patient with recurrent metastatic GIST.11 Immediately after surgical debulking, the serum glucose levels returned to normal without requiring further intravenous glucose treatment. The patient remained euglycemic and without imaging evidence of disease progression at the 6-month follow-up. Tumor analysis showed increased insulin-like growth factor II mRNA and its precursor mRNA. Similar cases of GIST-associated hypoglycemia have been reported.12-16 Furthermore, paraneoplastic cutaneous lesions with GIST have been described.17 Granuloma annulare (GA) is a rare cutaneous lesion that is characterized by annular erythematous plaques with raised borders and is diagnosed by clinical and histologic criteria. GA has been associated with malignancy, most notably lymphoma.18 Chiu et al17 reported a patient with generalized GA; evaluation revealed a localized gastric GIST. The patient underwent surgical resection with complete resolution of the GA.17 Our observation suggests that GIST tumors may produce ammonia and that a portosystemic shunt may be required for the clinical manifestation of hyperammonemic encephalopathy to become apparent.
Connie G. Chiu Cedars-Sinai Medical Center, Los Angeles; John Wayne Cancer Institute, Santa Monica, CA JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on September 16, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
Karen N. Zaghiyan and Allan W. Silberman Cedars-Sinai Medical Center, Los Angeles, CA
ACKNOWLEDGMENT
Supported in part by funding from the Robert J. and Suzanne Gottleib Endowment in Surgical Oncology (Los Angeles, CA), and the Surgical Oncology Education and Research Fund at Cedars-Sinai Medical Center. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Ferenci P, Lockwood A, Mullen K, et al: Hepatic encephalopathy: Definition, nomenclature, diagnosis, and quantification—Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716-721, 2002 2. Matsumoto K, Sawaki A, Mizuno N, et al: Clinical efficacy and safety of sunitinib after imatinib failure in Japanese patients with gastrointestinal stromal tumor. Jpn J Clin Oncol 41:57-62, 2011 3. Lee NR, Yhim HY, Yim CY, et al: Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors. Ann Pharmacother 45:e56, 2011 4. Nott L, Price TJ, Pittman K, et al: Hyperammonemia encephalopathy: An important cause of neurological deterioration following chemotherapy. Leuk Lymphoma 48:1702-1711, 2007 5. Liaw CC, Wang HM, Wang CH, et al: Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. Anticancer Drugs 10:275-281, 1999 6. Yeh KH, Cheng AL: Acute confusion induced by a high-dose infusion of 5-fluorouracil and folinic acid. J Formos Med Assoc 93:721-723, 1994
7. Yeh KH, Cheng AL: High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 75:464-465, 1997 8. Kwan L, Wang C, Levitt L: Hyperammonemic encephalopathy in multiple myeloma. N Engl J Med 346:1674-1675, 2002 9. Takimoto Y, Imanaka F, Hayashi Y, et al: A patient with ammonia-producing multiple myeloma showing hyperammonemic encephalopathy. Leukemia 10: 918-919, 1996 10. Otsuki T, Yamada O, Sakaguchi H, et al: In vitro excess ammonia production in human myeloma cell lines. Leukemia 12:1149-1158, 1998 11. Escobar GA, Robinson WA, Nydam TL, et al: Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: A case report. BMC Cancer 7:13, 2007 12. Hamberg P, de Jong FA, Boonstra JG, et al: Non-islet-cell tumor induced hypoglycemia in patients with advanced gastrointestinal stromal tumor possibly worsened by imatinib. J Clin Oncol 24:e30-e31, 2006 13. Pink D, Schoeler D, Lindner T, et al: Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: A report of two cases. J Clin Oncol 23:6809-6811, 2005 14. Beckers MM, Slee PH, van Doorn J: Hypoglycaemia in a patient with a gastrointestinal stromal tumour. Clin Endocrinol (Oxf) 59:402-404, 2003 15. Rikhof B, Van Den Berg G, Van Der Graaf WT: Non-islet cell tumour hypoglycaemia in a patient with a gastrointestinal stromal tumour. Acta Oncol 44:764-766, 2005 16. Guiteau J, Fanucchi M, Folpe A, et al: Hypoglycemia in the setting of advanced gastrointestinal stromal tumor. Am Surg 72:1225-1230, 2006 17. Chiu ML, Tang MB: Generalized granuloma annulare associated with gastrointestinal stromal tumour: Case report and review of clinical features and management. Clin Exp Dermatol 33:469-471, 2008 18. Li A, Hogan DJ, Sanusi ID, et al: Granuloma annulare and malignant neoplasms. Am J Dermatopathol 25:113-116, 2003
DOI: 10.1200/JCO.2013.48.9302; published online ahead of print at www.jco.org on June 30, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on September 16, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
3
Case Report The patient, an 81-year-old white man, had a history of GI stromal tumor (GIST) of the small bowel that was diagnosed in December 2005. At that time he underwent small bowel resection with complete surgical removal of the tumor. Pathologic evaluation revealed a 4-cm GIST with low mitotic rate and no regional lymph node involvement. Imaging revealed no distant metastatic disease. Thus, the patient did not receive adjuvant therapy. He remained disease free until January 2012. At that time, he presented with a 3-month history of progressive abdominal pain. Computed tomography (CT) imaging revealed an 11 ⫻ 9.5 ⫻ 8 – cm right abdominal mass. CT-guided biopsy confirmed recurrent GIST. The patient began receiving imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ). After 3 months of therapy, he required hospital admission for progressive confusion and weakness with no focal neurologic deficit. The serum ammonia level at that time was 171 mol/L (normal level, ⬍ 42 mol/L; Fig 1). Repeat imaging showed progression of disease with increased tumor size to 12 ⫻ 18 ⫻ 15 cm with surrounding varices (Fig 2A, red arrow) and multiple new intra-abdominal masses that were consistent with sarcomatosis. A portosystemic shunt was also noted between the varices from the tumor and the right renal vein (Fig 2B, red arrow) and renal cortex (Fig 2C, red arrow). There was no evidence of hepatic metastases or liver dysfunction. Using the consensus report of the Working Party at the 11th World Congresses of Gastroenterology,1 our patient would be classified as having type B encephalopathy, grade 2. Imatinib mesylate was discontinued and treatment with sunitinib malate (Sutent; Pfizer, New York, NY) was initiated in addition to lactulose therapy. The patient experienced moderate improvement in his mental status with corresponding improvement in his ammonia levels, although they never reached a normal level. He required emergent admission for profound encephalopathy (type B, grade 3) 2.5 months later. This was associated with a serum ammonia level of 155 mol/L (Fig 1) and progressive abdominal disease. Evaluation for other causes of encephalopathy and hyperammonemia was unrevealing. Assessment included serum hepatic function tests, serum metabolic levels, toxin screen, basic urea cycle enzyme levels, and urine amino acid levels. Brain magnetic resonance imaging was negative, and T1 signal hyperintensity in the basal ganglia was not demonstrated. Hepatic imaging was also negative. The patient continued to be confused and disoriented despite continued lactulose treatment and discontinuation of sunitinib malate. Because of the lack of improvement in mental status and the possibility that the tumor was the cause of the hyperammonemia, the patient underwent operative tumor debulking. Findings included a large multilobulated abdominal tumor with numerous surrounding varices (Fig 3) in addition to sarcomatosis involving the lower abdomen and pelvis. There was no evidence of liver metastases. The tumor Journal of Clinical Oncology, Vol 32, 2014
180
Serum Ammonia (µmol/L)
Hyperammonemic Encephalopathy Associated With GI Stromal Tumor
D I A G N O S I S
160 140
I N
* †
O N C O L O G Y
Surgical tumor debulking ‡
120 100 80 60 40 20 0
5/3 1/2 6/7 012 6/1 /201 4/ 2 6/2 201 1/2 2 6/2 01 8/2 2 7/5 012 7/1 /201 2/ 2 7/1 201 9 2 7/2 /201 6/2 2 8/2 012 / 8/9 2012 /20 8/1 1 6 2 8/2 /201 3/ 2 8/2 201 3/2 2 9/6 012 9/1 /201 3 2 9/2 /201 0/ 2 9/2 201 7 2 10 /201 /4/ 2 10 20 /11 12 /20 12
JOURNAL OF CLINICAL ONCOLOGY
Date Fig 1.
was removed in continuity with involved colon and small bowel along with debulking of peritoneal disease. Pathologic evaluation revealed a 14-cm GIST with 11 mitoses/50 high-power fields (hpf) and greater than 90% viable tumor. Tumor cells were strongly immunoreactive with CD117 (c-kit) and CD34 antibodies. Tumor cells were negative with S-100, desmin, and smooth muscle-specific actin antibodies. Platelet-derived growth factor receptor-␣ was not tested. The serum ammonia level in the recovery room 1 hour after surgery showed remarkable normalization to 33 mol/L (Fig 1) with return to normal mental status on postoperative day 1. The patient recovered from surgery and was discharged to return home. Serum ammonia levels remained normal with no recurrent encephalopathy 8 months after surgery. Discussion We describe a patient with hyperammonemic encephalopathy that was associated with GIST. The pathophysiologic mechanism may involve tumor production of ammonia and require a tumorportosystemic shunt to reveal encephalopathy. The preoperative CT imaging revealed tumor-related varices draining into the right renal vein (Fig 2B) and renal cortex (Fig 2C), supporting the concept of a portosystemic shunt for the development of hyperammonemia with resultant encephalopathy. In addition, the serum ammonia level was looselycorrelatedwithdiseaseburdeninthispatient,whichwasevidenced by progressive hyperammonemia that was associated with disease progressiononserialimaging,andrapidresolutionaftersurgicalresection.To our knowledge, this is the first report of an ammonia-secreting GIST tumor causing hyperammonemic encephalopathy. There have been several chemotherapeutic and targeted systemic agents in cancer therapy that are implicated in hyperammonemia, notably fluorouracil and sunitinib malate.2-7 In a Japanese report of 18 patients with advanced GIST treated with sunitinib malate after failure © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on September 16, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Chiu, Zaghiyan, and Silberman
A
B Fig 3.
C
Fig 2.
of imatinib mesylate therapy, one patient developed irreversible hyperammonemia and flapping tremor.2 The authors attributed this finding to sunitinib therapy and its antiangiogenic properties. However, the report also describes the identification of a portosystemic shunt on CT imaging of the patient. Alternatively, this finding would support the possibility of serum accumulation of ammonia that may be directly produced by the GIST. In another report, two patients presented with confusion and dramatic hyperammonemia that occurred at 17 and 10 days after initiation of sunitinib malate therapy for 2
© 2014 by American Society of Clinical Oncology
metastatic GIST.3 After treatment with lactulose enemas and discontinuation of sunitinib malate, both patients experienced improvement in mental status. Serum ammonia levels improved but did not return to normal. Sunitinib malate was restarted in one patient, resulting in recurrence of confusion and hyperammonemia after 7 days of therapy. Although the serum ammonia level and mental status change correlated closely with the timing of sunitinib malate therapy, resolution of these disturbances may have been attributable to treatment with lactulose enemas rather than discontinuation of sunitinib malate. In addition, both patients had continued demonstrable disease. Thus, hyperammonemia may have been the result of progressive tumor burden and may not have been caused by the sunitinib malate therapy. Indeed, multiple myeloma cells have been postulated to induce hyperammonemia as a result of altered amino acid metabolism.8-10 This same mechanism may be present in GIST and requires further study. There have been several paraneoplastic syndromes described in association with GIST.11-17 Severe symptomatic hypoglycemia was reported in a patient with recurrent metastatic GIST.11 Immediately after surgical debulking, the serum glucose levels returned to normal without requiring further intravenous glucose treatment. The patient remained euglycemic and without imaging evidence of disease progression at the 6-month follow-up. Tumor analysis showed increased insulin-like growth factor II mRNA and its precursor mRNA. Similar cases of GIST-associated hypoglycemia have been reported.12-16 Furthermore, paraneoplastic cutaneous lesions with GIST have been described.17 Granuloma annulare (GA) is a rare cutaneous lesion that is characterized by annular erythematous plaques with raised borders and is diagnosed by clinical and histologic criteria. GA has been associated with malignancy, most notably lymphoma.18 Chiu et al17 reported a patient with generalized GA; evaluation revealed a localized gastric GIST. The patient underwent surgical resection with complete resolution of the GA.17 Our observation suggests that GIST tumors may produce ammonia and that a portosystemic shunt may be required for the clinical manifestation of hyperammonemic encephalopathy to become apparent.
Connie G. Chiu Cedars-Sinai Medical Center, Los Angeles; John Wayne Cancer Institute, Santa Monica, CA JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on September 16, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
Karen N. Zaghiyan and Allan W. Silberman Cedars-Sinai Medical Center, Los Angeles, CA
ACKNOWLEDGMENT
Supported in part by funding from the Robert J. and Suzanne Gottleib Endowment in Surgical Oncology (Los Angeles, CA), and the Surgical Oncology Education and Research Fund at Cedars-Sinai Medical Center. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Ferenci P, Lockwood A, Mullen K, et al: Hepatic encephalopathy: Definition, nomenclature, diagnosis, and quantification—Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716-721, 2002 2. Matsumoto K, Sawaki A, Mizuno N, et al: Clinical efficacy and safety of sunitinib after imatinib failure in Japanese patients with gastrointestinal stromal tumor. Jpn J Clin Oncol 41:57-62, 2011 3. Lee NR, Yhim HY, Yim CY, et al: Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors. Ann Pharmacother 45:e56, 2011 4. Nott L, Price TJ, Pittman K, et al: Hyperammonemia encephalopathy: An important cause of neurological deterioration following chemotherapy. Leuk Lymphoma 48:1702-1711, 2007 5. Liaw CC, Wang HM, Wang CH, et al: Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. Anticancer Drugs 10:275-281, 1999 6. Yeh KH, Cheng AL: Acute confusion induced by a high-dose infusion of 5-fluorouracil and folinic acid. J Formos Med Assoc 93:721-723, 1994
7. Yeh KH, Cheng AL: High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 75:464-465, 1997 8. Kwan L, Wang C, Levitt L: Hyperammonemic encephalopathy in multiple myeloma. N Engl J Med 346:1674-1675, 2002 9. Takimoto Y, Imanaka F, Hayashi Y, et al: A patient with ammonia-producing multiple myeloma showing hyperammonemic encephalopathy. Leukemia 10: 918-919, 1996 10. Otsuki T, Yamada O, Sakaguchi H, et al: In vitro excess ammonia production in human myeloma cell lines. Leukemia 12:1149-1158, 1998 11. Escobar GA, Robinson WA, Nydam TL, et al: Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: A case report. BMC Cancer 7:13, 2007 12. Hamberg P, de Jong FA, Boonstra JG, et al: Non-islet-cell tumor induced hypoglycemia in patients with advanced gastrointestinal stromal tumor possibly worsened by imatinib. J Clin Oncol 24:e30-e31, 2006 13. Pink D, Schoeler D, Lindner T, et al: Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: A report of two cases. J Clin Oncol 23:6809-6811, 2005 14. Beckers MM, Slee PH, van Doorn J: Hypoglycaemia in a patient with a gastrointestinal stromal tumour. Clin Endocrinol (Oxf) 59:402-404, 2003 15. Rikhof B, Van Den Berg G, Van Der Graaf WT: Non-islet cell tumour hypoglycaemia in a patient with a gastrointestinal stromal tumour. Acta Oncol 44:764-766, 2005 16. Guiteau J, Fanucchi M, Folpe A, et al: Hypoglycemia in the setting of advanced gastrointestinal stromal tumor. Am Surg 72:1225-1230, 2006 17. Chiu ML, Tang MB: Generalized granuloma annulare associated with gastrointestinal stromal tumour: Case report and review of clinical features and management. Clin Exp Dermatol 33:469-471, 2008 18. Li A, Hogan DJ, Sanusi ID, et al: Granuloma annulare and malignant neoplasms. Am J Dermatopathol 25:113-116, 2003
DOI: 10.1200/JCO.2013.48.9302; published online ahead of print at www.jco.org on June 30, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on September 16, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
3
