Clinical Review & Education
JAMA Surgery Clinical Challenge
Bleeding Abdominal Mass in a Patient With Genetic Cutaneous Disorder Shawn S. Fu, MD; Jeffrey A. McDavit, MD; Ilia Gur, MD
A
B
Figure 1. A, Multiple cutaneous nodules and pigmented spots are evident on physical examination. B, Cross-sectional imaging reveals a large, complex, septated, right-upper-quadrant abdominal mass.
A 72-year-old man presented to the hospital after sustaining a fall, with prior generalized weakness and fatigue. He had been having recurrent gastrointestinal bleeding and melena during the past year. He reported a 6.75-kg weight loss during the past few months but did not have abdominal pain, nausea, vomiting, fevers, or chills. His surgical history was notable for a coronary artery bypass graft 9 months earlier and γ-knife resection of an acoustic neuroma 10 years ago. Physical examination revealed a soft, nontender abdomen without obvious palpable masses. Inspection of the patient’s skin demonstrated multiple fleshy, soft cutaneous nodules (Figure 1A). The patient’s laboratory testing was only notable for anemia with a hemoglobin level of 10.4 g/dL (reference range, 12-16 g/dL). A prior extensive examination, including upper and lower endoscopy, upper gastrointestinal series with small-bowel follow-through, and capsule endoscopy did not reveal a diagnosis. A computed tomography image of the abdomen and pelvis is shown in Figure 1B.
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WHAT IS THE DIAGNOSIS?
A. Carcinoid tumor B. Gastrointestinal stromal tumor C. Neurofibroma D. Intra-abdominal abscess
JAMA Surgery November 2014 Volume 149, Number 11
Copyright 2014 American Medical Association. All rights reserved.
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Clinical Review & Education JAMA Surgery Clinical Challenge
Diagnosis B. Gastrointestinal stromal tumor
Discussion This patient has neurofibromatosis type 1 (NF1). These patients have a high incidence of cutaneous and neural tumors, as suggested by the history of acoustic neuroma and dermal neurofibromas seen on examination. Computed tomographic imaging demonstrated a large, septated mass arising from the duodenum. A retroperitoneal needle biopsy demonstrated a spindle-cell tumor, and immunohistochemical staining was positive for CD117 (C-KIT) and CD34 (plateletderived growth factor receptor α [PDGFR-α]), indicative of a gastrointestinal stromal tumor (GIST). As discussed below, NF1 patients have a high incidence of a special type of GIST, uniquely lacking C-KIT mutations, thereby causing resistance to imatinib mesylate therapy. Hence,surgicalresectionisthemosteffectivetreatmentinthesecases. During surgical exploration, a large, encapsulated mass (15 x 11 x 7.5 cm) was found arising from the lateral aspect of the second portion of the duodenum (Figure 2). Because of this location, a pancreaticoduodenectomy was necessary to render the patient disease-free. Pathologic analysis demonstrated negative margins and a high-grade lesion, with 15 mitotic figures per 50 high-powerfields. The patient recovered appropriately from his surgery and was discharged home.
Figure 2. The final resected specimen. The gastrointestinal stromal tumor is seen arising from the second portion of the duodenum.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: Department of Surgery, San Joaquin General Hospital, French Camp, California (Fu); Department of Pathology, St Joseph’s Medical Center, Stockton, California (McDavit); Department of Surgery, Sutter Gould Medical Foundation, Stockton, California (Gur).
1. Kingham TP, DeMatteo RP. Multidisciplinary treatment of gastrointestinal stromal tumors. Surg Clin North Am. 2009;89(1):217-233.
Corresponding Author: Shawn S. Fu, MD, Department of Surgery, San Joaquin General Hospital, 500 W Hospital Rd, French Camp, CA 95231 ([email protected]). Section Editor: Jonathan R. Hiatt, MD. Accepted for Publication: October 29, 2013. Published Online: September 24, 2014. doi:10.1001/jamasurg.2013.5701. Conflict of Interest Disclosures: None reported.
1204
This case highlights the disparity between immunohistochemical and molecular definitions of GISTs, and the growing complexity of our understanding of its pathophysiology. GISTs represent a variety of mesenchymal tumors of the gastrointestinal tract. As exemplified by our patient, spindle-cell histology and GI bleeding are common findings.1 Originally thought of as variants of leiomyomas or leiomyosarcomas, GISTs have been redefined due to advances in immunohistochemical staining, with nearly 95% expressing either CD117 (CKIT) or CD34 (PDGFR-α).1 With advances in molecular biology, we now know that C-KIT and PDGFR-α are tyrosine kinase receptors heavily involved in cell signaling. Molecular analysis of most GISTs demonstrates “gain-of-function” mutations that constitutively activate these receptors, thus activating downstream RAS-MAP kinase pathways, promoting uncontrolled growth2,3 Most of these mutations are wellcharacterized and map to certain exons in the C-KIT and PDGFR-␣ genes. These C-KIT and PDGFR-α receptors are specifically targeted by tyrosine kinase inhibitors such as imatinib, which has led to revolutionary treatment options for unresectable and metastatic GIST.1 Neurofibromatosis type 1 shares a unique association with GIST, with the incidence of GIST in NF1 patients ranging from 5-25% in population-based studies.3,4 Although most NF1-associated GISTs demonstrate positive immunohistochemical staining for C-KIT, molecular analysis of these tumors shows that most express wild-type C-KIT and PDGFR-α receptors, which do not share the same mutations typically seen in non-NF1 sporadic GISTs.2,5 These wild-type receptors behave differently than the hyperactivated receptors typically found in non-NF1 GISTs, and the result is near-complete insensitivity to antityrosine kinase therapy, despite positive immunohistochemical staining for C-KIT.2 Interestingly, NF1 is caused by a defect in the neurofibromin gene, which is a negative regulator of the RAS-Map kinase pathway.2,6 Thus, presumably the same downstream pathways are ultimately dysregulated in NF1 GIST disease, albeit by a different inciting mechanism – one which bypasses C-KIT and PDGFR-α.2,6 As a result, imatinib is typically ineffective in the treatment of NF1associated GISTs. Indeed, molecular analysis confirmed that our patient had none of the typical C-KIT or PDGFR-α mutations seen in nonNF1 GISTs; therefore, resection was the only treatment option. As our understanding of the molecular biology behind GISTs evolves, mutational analysis has become increasingly important because of its ability to predict response to imatinib therapy.7,8 Six months after surgery, the patient remains disease-free.
2. Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res. 2008;14(14):4550-4555. 3. Agaimy A, Vassos N, Croner RS. Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen’s disease). Int J Clin Exp Pathol. 2012;5(9):852-862. 4. Relles D, Baek J, Witkiewicz A, Yeo CJ. Periampullary and duodenal neoplasms in neurofibromatosis type 1. J Gastrointest Surg. 2010; 14(6):1052-1061.
5. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53(3):245-266. 6. Cavallaro G, Basile U, Polistena A, et al. Surgical management of abdominal manifestations of type 1 neurofibromatosis. Am Surg. 2010;76(4):389-396. 7. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report. J Natl Compr Canc Netw. 2010;8(2)(suppl 2):S1-S44. 8. Casali PG, Blay JY; ESMO/CONTICANET/ EUROBONET Consensus Panel of Experts. Gastrointestinal stromal tumours. Ann Oncol. 2010; 21(5)(suppl 5):v98-v102.
JAMA Surgery November 2014 Volume 149, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Cornell University User on 09/05/2016
jamasurgery.com
JAMA Surgery Clinical Challenge
Bleeding Abdominal Mass in a Patient With Genetic Cutaneous Disorder Shawn S. Fu, MD; Jeffrey A. McDavit, MD; Ilia Gur, MD
A
B
Figure 1. A, Multiple cutaneous nodules and pigmented spots are evident on physical examination. B, Cross-sectional imaging reveals a large, complex, septated, right-upper-quadrant abdominal mass.
A 72-year-old man presented to the hospital after sustaining a fall, with prior generalized weakness and fatigue. He had been having recurrent gastrointestinal bleeding and melena during the past year. He reported a 6.75-kg weight loss during the past few months but did not have abdominal pain, nausea, vomiting, fevers, or chills. His surgical history was notable for a coronary artery bypass graft 9 months earlier and γ-knife resection of an acoustic neuroma 10 years ago. Physical examination revealed a soft, nontender abdomen without obvious palpable masses. Inspection of the patient’s skin demonstrated multiple fleshy, soft cutaneous nodules (Figure 1A). The patient’s laboratory testing was only notable for anemia with a hemoglobin level of 10.4 g/dL (reference range, 12-16 g/dL). A prior extensive examination, including upper and lower endoscopy, upper gastrointestinal series with small-bowel follow-through, and capsule endoscopy did not reveal a diagnosis. A computed tomography image of the abdomen and pelvis is shown in Figure 1B.
jamasurgery.com
WHAT IS THE DIAGNOSIS?
A. Carcinoid tumor B. Gastrointestinal stromal tumor C. Neurofibroma D. Intra-abdominal abscess
JAMA Surgery November 2014 Volume 149, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Cornell University User on 09/05/2016
1203
Clinical Review & Education JAMA Surgery Clinical Challenge
Diagnosis B. Gastrointestinal stromal tumor
Discussion This patient has neurofibromatosis type 1 (NF1). These patients have a high incidence of cutaneous and neural tumors, as suggested by the history of acoustic neuroma and dermal neurofibromas seen on examination. Computed tomographic imaging demonstrated a large, septated mass arising from the duodenum. A retroperitoneal needle biopsy demonstrated a spindle-cell tumor, and immunohistochemical staining was positive for CD117 (C-KIT) and CD34 (plateletderived growth factor receptor α [PDGFR-α]), indicative of a gastrointestinal stromal tumor (GIST). As discussed below, NF1 patients have a high incidence of a special type of GIST, uniquely lacking C-KIT mutations, thereby causing resistance to imatinib mesylate therapy. Hence,surgicalresectionisthemosteffectivetreatmentinthesecases. During surgical exploration, a large, encapsulated mass (15 x 11 x 7.5 cm) was found arising from the lateral aspect of the second portion of the duodenum (Figure 2). Because of this location, a pancreaticoduodenectomy was necessary to render the patient disease-free. Pathologic analysis demonstrated negative margins and a high-grade lesion, with 15 mitotic figures per 50 high-powerfields. The patient recovered appropriately from his surgery and was discharged home.
Figure 2. The final resected specimen. The gastrointestinal stromal tumor is seen arising from the second portion of the duodenum.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: Department of Surgery, San Joaquin General Hospital, French Camp, California (Fu); Department of Pathology, St Joseph’s Medical Center, Stockton, California (McDavit); Department of Surgery, Sutter Gould Medical Foundation, Stockton, California (Gur).
1. Kingham TP, DeMatteo RP. Multidisciplinary treatment of gastrointestinal stromal tumors. Surg Clin North Am. 2009;89(1):217-233.
Corresponding Author: Shawn S. Fu, MD, Department of Surgery, San Joaquin General Hospital, 500 W Hospital Rd, French Camp, CA 95231 ([email protected]). Section Editor: Jonathan R. Hiatt, MD. Accepted for Publication: October 29, 2013. Published Online: September 24, 2014. doi:10.1001/jamasurg.2013.5701. Conflict of Interest Disclosures: None reported.
1204
This case highlights the disparity between immunohistochemical and molecular definitions of GISTs, and the growing complexity of our understanding of its pathophysiology. GISTs represent a variety of mesenchymal tumors of the gastrointestinal tract. As exemplified by our patient, spindle-cell histology and GI bleeding are common findings.1 Originally thought of as variants of leiomyomas or leiomyosarcomas, GISTs have been redefined due to advances in immunohistochemical staining, with nearly 95% expressing either CD117 (CKIT) or CD34 (PDGFR-α).1 With advances in molecular biology, we now know that C-KIT and PDGFR-α are tyrosine kinase receptors heavily involved in cell signaling. Molecular analysis of most GISTs demonstrates “gain-of-function” mutations that constitutively activate these receptors, thus activating downstream RAS-MAP kinase pathways, promoting uncontrolled growth2,3 Most of these mutations are wellcharacterized and map to certain exons in the C-KIT and PDGFR-␣ genes. These C-KIT and PDGFR-α receptors are specifically targeted by tyrosine kinase inhibitors such as imatinib, which has led to revolutionary treatment options for unresectable and metastatic GIST.1 Neurofibromatosis type 1 shares a unique association with GIST, with the incidence of GIST in NF1 patients ranging from 5-25% in population-based studies.3,4 Although most NF1-associated GISTs demonstrate positive immunohistochemical staining for C-KIT, molecular analysis of these tumors shows that most express wild-type C-KIT and PDGFR-α receptors, which do not share the same mutations typically seen in non-NF1 sporadic GISTs.2,5 These wild-type receptors behave differently than the hyperactivated receptors typically found in non-NF1 GISTs, and the result is near-complete insensitivity to antityrosine kinase therapy, despite positive immunohistochemical staining for C-KIT.2 Interestingly, NF1 is caused by a defect in the neurofibromin gene, which is a negative regulator of the RAS-Map kinase pathway.2,6 Thus, presumably the same downstream pathways are ultimately dysregulated in NF1 GIST disease, albeit by a different inciting mechanism – one which bypasses C-KIT and PDGFR-α.2,6 As a result, imatinib is typically ineffective in the treatment of NF1associated GISTs. Indeed, molecular analysis confirmed that our patient had none of the typical C-KIT or PDGFR-α mutations seen in nonNF1 GISTs; therefore, resection was the only treatment option. As our understanding of the molecular biology behind GISTs evolves, mutational analysis has become increasingly important because of its ability to predict response to imatinib therapy.7,8 Six months after surgery, the patient remains disease-free.
2. Mussi C, Schildhaus HU, Gronchi A, Wardelmann E, Hohenberger P. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res. 2008;14(14):4550-4555. 3. Agaimy A, Vassos N, Croner RS. Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen’s disease). Int J Clin Exp Pathol. 2012;5(9):852-862. 4. Relles D, Baek J, Witkiewicz A, Yeo CJ. Periampullary and duodenal neoplasms in neurofibromatosis type 1. J Gastrointest Surg. 2010; 14(6):1052-1061.
5. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53(3):245-266. 6. Cavallaro G, Basile U, Polistena A, et al. Surgical management of abdominal manifestations of type 1 neurofibromatosis. Am Surg. 2010;76(4):389-396. 7. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report. J Natl Compr Canc Netw. 2010;8(2)(suppl 2):S1-S44. 8. Casali PG, Blay JY; ESMO/CONTICANET/ EUROBONET Consensus Panel of Experts. Gastrointestinal stromal tumours. Ann Oncol. 2010; 21(5)(suppl 5):v98-v102.
JAMA Surgery November 2014 Volume 149, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Cornell University User on 09/05/2016
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