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Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib

Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with... Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2015, Article ID 317493, 5 pages http://dx.doi.org/10.1155/2015/317493 Case Report Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib 1 2 1 3 Xiaoyin Jiang, H. Bryan Anderson, Cynthia D. Guy, Paul J. Mosca, 4 1 Richard F. Riedel, and Diana M. Cardona Department of Pathology, Duke University,DUMCBox 3712,Durham, NC 27710, USA St. George’s University, St. George, Grenada Department of Surgery, Duke University, 3116 North Duke Street, Durham, NC 27704, USA Department of Medicine,DukeUniversity, DUMC Box3198, Durham,NC27710,USA Correspondence should be addressed to Xiaoyin Jiang; jiang009@mc.duke.edu Received 22 July 2014; Accepted 14 December 2014 Academic Editor: Cesar V. Reyes Copyright © 2015 Xiaoyin Jiang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rhabdomyosarcomatous dedifferentiation of GIST following tyrosine kinase inhibitor (TKI) therapy is rare, with only a handful of cases previously reported in the literature. Herein we present a case of metastatic GIST initially treated with imatinib that developed radiographic evidence of progression aer ft 8 months of standard dose therapy with continued progression despite attempts at using dose-escalated imatinib 400 mg bid. Due to the patient’s worsening clinical symptoms and radiographic concerns for colonic thickening, abscess, and extraluminal air, the patient underwent a palliative resection of a large heterogeneous mass arising from the posterior stomach and several metastatic foci. Pathology revealed a dedifferentiated GIST with rhabdomyosarcomatous features. This report will highlight the unique features of this case and review the existing literature. 1. Introduction metastatic disease based on data from Demetri et al. showing sustained objective response in more than half of patients Gastrointestinal stromal tumors (GISTs) are the most com- treated [7]. This potential drug response is most efficacious mon mesenchymal tumors of the alimentary tract. GISTs in those tumor harboring exon 11 Kit mutations, while those most commonly affect adults over the age of 50 with a with exon 9 mutations showed worse prognosis and benefited slight male predominance [1]. These neoplasms are believed more from higher-dose therapy [8]. to arise from the interstitial cells of Cajal and over 80% Herein we report a case of metastatic GIST with rhab- express CD117 (c-Kit) by immunohistochemistry (IHC) [2]. domyosarcomatous transformation following treatment with Characteristically these neoplasms contain activating muta- imatinib. tions in KIT, or less commonly platelet derived growth factor receptor alpha (PDGFRA). These genetic alterations result in 2. Materials and Methods a gain of function or constitutive activation of the encoded tyrosine kinases [1]. Morphologically, GISTs are composed Surgical specimens were xfi ed in 10% neutral buffered for- of spindle, epithelioid, or rarely pleomorphic cells and most malin. Following xa fi tion gross examination was performed commonly also express CD34 and DOG1 antigens by IHC and representative sections were embedded in paran. ffi Five [2, 3]. Interestingly, relatively recent reports of rhabdoid micron thick hematoxylin and eosin stained sections were or rhabdomyosarcomatous (RMS) differentiation have been created. Immunohistochemistry for CD117 (rabbit mono- described in these tumors [4–6]. clonal, Cell Marque, Rocklin, CA), CD34 (clone MY10, Imatinib, a tyrosine kinase inhibitor (TKI), is the current BD Biosciences, San Jose, CA), DOG1 (clone K9, Leica mainstay of treatment for individuals with unresectable or Biosystems, Buffalo Grove, IL), desmin (clone DE-R-11, Leica 2 Case Reports in Oncological Medicine [A] [A] [P] [P] (a) (b) [A] [P] (c) Figure 1: CT scans from three time points showing a gastric mass. (a) Initial presentation. (b) Following 5 months of imatinib therapy. Note tumor response as compared to (a). (c) Following 10 months of imatinib therapy. Note tumor progression (tumor circled). Biosystems), smooth muscle actin (clone alpha sm-1, Leica mutations. Two months after initiation of treatment, however, Biosystems), myoD1 (clone 5.8A, Dako, Carpinteria, CA), there was radiographic evidence of treatment response with and myogenin (clone F5D, Dako) was performed. Molecular a significant decrease in size of all tumors ( Figure 1(b)). analysis for KIT mutation was performed at an outside Eightmonthsaeft rinitiationofimatinibCTimaging laboratory (OHSU, Portland, OR) using DNA extraction and demonstrated tumor regrowth and heterogeneous enhance- puricfi ation of paraffin embedded tumor tissue. ment at the primary tumor site while other metastatic sites remained stable. eTh dose of imatinib was subsequently escalated to 800 mg daily (400 mg bid). 3. Results Approximately one year aer ft his initial presentation, the patient presented with upper gastrointestinal bleeding and 3.1. Clinical History. A 47-year-old African American male an associated microperforation due to tumor progression presented to the emergency department with complaints (Figure 1(c)). Given concerns for abscess and developing of right lower quadrant abdominal pain and a 20-pound fistula by imaging, a palliative surgical procedure was under- weight loss over the prior two months. eTh patient had no taken and included en bloc resection of the tumor with signicfi ant past medical history or any other symptomatology. a total gastrectomy/Roux-en-Y esophagojejunostomy, distal Computerized tomography (CT) imaging revealed a 14 cm pancreatectomy, splenectomy, left partial hepatectomy, and tumor with possible central necrosis that originated from extended right colectomy. the posterior gastric wall and extended superiorly to the diaphragm (Figure 1(a)). Additionally, there appeared to be metastases in the right pelvic cavity (5.5 cm) and within a 3.2. Histopathological Diagnosis and Genetic Analysis. The right inguinal hernia (4.5 cm). An endoscopic biopsy of the resection revealed a 10.4× 6.4×6.3 cmtumorarisingfromthe gastric lesion revealed a spindle cell neoplasm which was stomach and invading into the spleen and pancreas. eTh bulk strongly and diffusely immunoreactive for CD117, CD34, and of the tumor was composed of pleomorphic, eosinophilic DOG1. S-100 protein, smooth muscle actin, desmin, and polygonal cells with bizarre nuclei, abundant cytoplasm, and cyokeratin IHC were negative. The diagnosis of GIST was increased mitotic activity (up to 3 mitotic gur fi es per 50 rendered. eTh patient was initiated on imatinib 400 mg daily. high power elds) fi ( Figure 2(b)). Also observed were areas Initial molecular testing was negative for exon 9 or exon 11 of marked hyalinization, consistent with treatment eeff ct, Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) Figure 2: Tumor at the time of en bloc resection. Left panels showing H&E (a, b) and immunophenotype of spindle cell component (a, c, e, g, and i) and right panels showing rhabdomyosarcomatous component (b, d, f, h, and j) as follows: (c, d) c-kit IHC, 200x, (e, f) DOG1 IHC, 200x, (g, h) desmin IHC, 200x, and (i, j) myoD-1, 400x. 4 Case Reports in Oncological Medicine and focal areas (<5% of the lesion) of a spindle cell tumor Curiously, the initial biopsy in our case was negative reminiscent of his previously biopsied GIST (Figure 2(a)). for KIT and PDGFRA mutations. This possibly represents a false negative result as the tumor was initially objectively eTh pleomorphic tumor cells were strongly positive for responsive to therapy, and tumors have not previously been desmin and focally positive for myoD1 but negative for reported to gain a primary-type (exon 9 or 11) mutation upon myogen (Myf-4), CD117, CD34, and DOG1 IHC, suggesting progression. rhabdomyosarcomatous differentiation. Inversely, the spindle With regard to therapy, sunitinib and regorafenib are cell component was positive for CD117, DOG1, and CD34 and approved therapies in the second and third lines, respectively, negative for the RMS antigens by IHC (Figures 2(c)–2(j)). but both have demonstrated only limited success [11–13]. A diagnosis of a dedifferentiated GIST with rhabdomyosar- Novel adjunct therapies targeting protein products down- comatous differentiation was made. Molecular testing for stream of KIT, such as PI3-K and MAPK/MEK, have been KIT mutations was performed on the two distinct histologic suggested, but to date these therapies have not become areas and both revealed an exon 11 deletion KV558-559. widely accepted or available [14]. Insucffi ient data exists on No imatinib resistance mutations were detected in exon whether standard rhabdomyosarcoma treatments such as 13, 17, or 18. Additionally, multiple brot fi ic omental nod- dactinomycin, vincristine, and cyclophosphamide would be ules (up to 1.4 cm) were resected at this time. These were more beneficial than TKIs for patients with dedifferentiated morphologically consistent with GISTs with marked tumor GISTs. response to imatinib treatment. No rhabdomyosarcomatous dieff rentiation was seen in these separate tumors. eTh patient 5. Conclusions was reinitiated on imatinib 400 mg daily and has remained on that dose for the past 4 years with evidence of stable disease. In summary, we report a genetically unique case of rhab- domyosarcomatous dedifferentiation in a GIST following TKI therapy. Our case supports prior reports that these 4. Discussion tumors behave in an aggressive fashion with early recurrence To ourknowledge,only6casesofrhabdomyosarcomatous and resistance to TKI treatment. The molecular ndings fi dedifferentiation in GISTs have been reported following suggestthattheresistancetoTKItherapyintheseraretumors is driven more by alternative mechanisms than through treatment with TKIs [4, 5]. Heterologous differentiation of secondary Kit/PDGFRA mutations. Further study is needed the primary tumor (as opposed to the metastases) has only to clarify these mechanisms as well as determine optimal been reported in 1 other case. This is the rfi st report of the treatment strategies. exon 11 deletion KV558-559 in this clinical setting. The rare cases of dedifferentiated tumors have generally demonstrated a more aggressive clinical course, with recur- Conflict of Interests rence and metastases. This stands in contrast to primary eTh authors declare that they have no conflict of interests. GISTs with rhabdoid morphology, which, although also uncommon, have not demonstrated malignant behavior [6, References 9]. Based on the small number of previously reported cases, [1] C. L. Corless, J. A. Fletcher, and M. C. Heinrich, “Biology of dedifferentiated tumors, as in our case, demonstrate resis- gastrointestinal stromal tumors,” Journal of Clinical Oncology, tance to the currently available TKI therapy. Time to treat- vol. 22, no. 18, pp. 3813–3825, 2004. ment failure in these rare tumors with RMS dedifferentiation [2] M. Miettinen and J. Lasota, “Gastrointestinal stromal tumors: ranged from 10 to 24 months [4, 5]. Our patient had only 8 review on morphology, molecular pathology, prognosis, and months of stable disease following TKI therapy. differential diagnosis,” Archives of Pathology and Laboratory In general, when treatment failure occurs, a unique Medicine,vol.130,no. 10,pp. 1466–1478, 2006. [3] M. D´ıaz Delgado, A. Hernandez ´ Amate, S. Pereira Gallardo, pattern of disease progression follows, termed a “resistant S. Jaramillo, J. A. Virizuela Echaburu, and R. J. Gonzalez- ´ nodule.” These nodules are seen on imaging as new cen- Cam ´ pora, “Gastrointestinal stromal tumors: morphological, tral or peripheral areas of enhancement within preexisting immunohistochemical and molecular changes associated with responding lesions. eTh se imatinib “resistant nodules” appear kinase inhibitor therapy,” Pathology and Oncology Research,vol. in about 50% of patients aer ft two years of therapy and are 17,no. 3, pp.455–461,2011. frequently found to have novel mutations in KIT or PDGFR [4] B. Liegl, J. L. Hornick, C. R. Antonescu, C. L. Corless, and (that were not present in the primary tumor). These findings C. D. M. Fletcher, “Rhabdomyosarcomatous differentiation in support the hypothesis that “resistant nodules” arise through gastrointestinal stromal tumors aeft r tyrosine kinase inhibitor clonal evolution [10]. However, of the reported GISTs with therapy: a novel form of tumor progression,” The American RMS dedifferentiation, only 1 of 6 has shown secondary KIT Journal of Surgical Pathology,vol.33, no.2,pp. 218–226, 2009. or PDGFR mutations [4]. The remaining vfi e, as in our case, [5] S.Zheng,K.-E. Huang, J. Jia, X. Li,and D.-Y.Tao,“Rhab- have only shown primary-type exon 11 mutations. This has led domyosarcomatous differentiation in gastrointestinal stromal to the proposition that the dedieff rentiation may be related to tumors aer ft imatinib resistance: a potential diagnostic pitfall,” an alternative mechanism for TKI resistance, the genetic basis Experimental Biology and Medicine,vol.238,no. 1, pp.120–124, of which has yet to be established. 2013. Case Reports in Oncological Medicine 5 [6] I.-M. Schaefer, P. Strob ¨ el, S. Cameron et al., “Rhabdoid mor- phology in gastrointestinal stromal tumours (GISTs) is associ- ated with PDGFRA mutations but does not imply aggressive behaviour,” Histopathology,vol.64, no.3,pp. 421–430, 2014. [7] G.D.Demetri,M.VonMehren,C.D.Blankeetal.,“Efficacyand safety of imatinib mesylate in advanced gastrointestinal stromal tumors,” eTh New England Journal of Medicine ,vol.347,no.7,pp. 472–480, 2002. [8] M. van Glabbeke, “Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients,” Journal of Clinical Oncology,vol.28, no.7,pp. 1247–1253, 2010. [9] J.A.Hanson, J. C. Trent, D. Yang,and K. Cooper,“Small- intestinal rhabdoid gastrointestinal stromal tumor (GIST): mutation analysis and clinical implications of a rare morpho- logical variant,” International Journal of Surgical Pathology,vol. 19, no. 5, pp. 653–657, 2011. [10] J. Desai, S. Shankar, M. C. Heinrich et al., “Clonal evolution of resistance to imatinib in patients with metastatic gastrointesti- nal stromal tumors,” Clinical Cancer Research,vol.13, no.18, pp. 5398–5405, 2007. [11] G. D. Demetri, M. C. Heinrich, J. A. Fletcher et al., “Molecular target modulation, imaging, and clinical evaluation of gastroin- testinal stromal tumor patients treated with sunitinib malate aer ft imatinib failure,” Clinical Cancer Research,vol.15, no.18, pp. 5902–5909, 2009. [12] H. Joensuu, F. de Braud, P. Coco et al., “Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate,” Annals of Oncology,vol.19, no.1,pp. 173–177, 2008. [13] G. D. Demetri, P. Reichardt, Y.-K. Kang et al., “Effi cacy and safety of regorafenib for advanced gastrointestinal stromal tumours aeft r failure of imatinib and sunitinib (GRID): an inter- national, multicentre, randomised, placebo-controlled, phase 3 trial,” The Lancet , vol. 381, no. 9863, pp. 295–302, 2013. [14] C. R. Antonescu, “eTh GIST paradigm: lessons for other kinase- driven cancers,” The Journal of Pathology ,vol.223,no.2,pp.251– 261, 2011. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Pubmed Central

Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib

Case Reports in Oncological Medicine , Volume 2015 – Jan 28, 2015

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Pubmed Central
Copyright
Copyright © 2015 Xiaoyin Jiang et al.
ISSN
2090-6706
eISSN
2090-6714
DOI
10.1155/2015/317493
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Abstract

Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2015, Article ID 317493, 5 pages http://dx.doi.org/10.1155/2015/317493 Case Report Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib 1 2 1 3 Xiaoyin Jiang, H. Bryan Anderson, Cynthia D. Guy, Paul J. Mosca, 4 1 Richard F. Riedel, and Diana M. Cardona Department of Pathology, Duke University,DUMCBox 3712,Durham, NC 27710, USA St. George’s University, St. George, Grenada Department of Surgery, Duke University, 3116 North Duke Street, Durham, NC 27704, USA Department of Medicine,DukeUniversity, DUMC Box3198, Durham,NC27710,USA Correspondence should be addressed to Xiaoyin Jiang; jiang009@mc.duke.edu Received 22 July 2014; Accepted 14 December 2014 Academic Editor: Cesar V. Reyes Copyright © 2015 Xiaoyin Jiang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rhabdomyosarcomatous dedifferentiation of GIST following tyrosine kinase inhibitor (TKI) therapy is rare, with only a handful of cases previously reported in the literature. Herein we present a case of metastatic GIST initially treated with imatinib that developed radiographic evidence of progression aer ft 8 months of standard dose therapy with continued progression despite attempts at using dose-escalated imatinib 400 mg bid. Due to the patient’s worsening clinical symptoms and radiographic concerns for colonic thickening, abscess, and extraluminal air, the patient underwent a palliative resection of a large heterogeneous mass arising from the posterior stomach and several metastatic foci. Pathology revealed a dedifferentiated GIST with rhabdomyosarcomatous features. This report will highlight the unique features of this case and review the existing literature. 1. Introduction metastatic disease based on data from Demetri et al. showing sustained objective response in more than half of patients Gastrointestinal stromal tumors (GISTs) are the most com- treated [7]. This potential drug response is most efficacious mon mesenchymal tumors of the alimentary tract. GISTs in those tumor harboring exon 11 Kit mutations, while those most commonly affect adults over the age of 50 with a with exon 9 mutations showed worse prognosis and benefited slight male predominance [1]. These neoplasms are believed more from higher-dose therapy [8]. to arise from the interstitial cells of Cajal and over 80% Herein we report a case of metastatic GIST with rhab- express CD117 (c-Kit) by immunohistochemistry (IHC) [2]. domyosarcomatous transformation following treatment with Characteristically these neoplasms contain activating muta- imatinib. tions in KIT, or less commonly platelet derived growth factor receptor alpha (PDGFRA). These genetic alterations result in 2. Materials and Methods a gain of function or constitutive activation of the encoded tyrosine kinases [1]. Morphologically, GISTs are composed Surgical specimens were xfi ed in 10% neutral buffered for- of spindle, epithelioid, or rarely pleomorphic cells and most malin. Following xa fi tion gross examination was performed commonly also express CD34 and DOG1 antigens by IHC and representative sections were embedded in paran. ffi Five [2, 3]. Interestingly, relatively recent reports of rhabdoid micron thick hematoxylin and eosin stained sections were or rhabdomyosarcomatous (RMS) differentiation have been created. Immunohistochemistry for CD117 (rabbit mono- described in these tumors [4–6]. clonal, Cell Marque, Rocklin, CA), CD34 (clone MY10, Imatinib, a tyrosine kinase inhibitor (TKI), is the current BD Biosciences, San Jose, CA), DOG1 (clone K9, Leica mainstay of treatment for individuals with unresectable or Biosystems, Buffalo Grove, IL), desmin (clone DE-R-11, Leica 2 Case Reports in Oncological Medicine [A] [A] [P] [P] (a) (b) [A] [P] (c) Figure 1: CT scans from three time points showing a gastric mass. (a) Initial presentation. (b) Following 5 months of imatinib therapy. Note tumor response as compared to (a). (c) Following 10 months of imatinib therapy. Note tumor progression (tumor circled). Biosystems), smooth muscle actin (clone alpha sm-1, Leica mutations. Two months after initiation of treatment, however, Biosystems), myoD1 (clone 5.8A, Dako, Carpinteria, CA), there was radiographic evidence of treatment response with and myogenin (clone F5D, Dako) was performed. Molecular a significant decrease in size of all tumors ( Figure 1(b)). analysis for KIT mutation was performed at an outside Eightmonthsaeft rinitiationofimatinibCTimaging laboratory (OHSU, Portland, OR) using DNA extraction and demonstrated tumor regrowth and heterogeneous enhance- puricfi ation of paraffin embedded tumor tissue. ment at the primary tumor site while other metastatic sites remained stable. eTh dose of imatinib was subsequently escalated to 800 mg daily (400 mg bid). 3. Results Approximately one year aer ft his initial presentation, the patient presented with upper gastrointestinal bleeding and 3.1. Clinical History. A 47-year-old African American male an associated microperforation due to tumor progression presented to the emergency department with complaints (Figure 1(c)). Given concerns for abscess and developing of right lower quadrant abdominal pain and a 20-pound fistula by imaging, a palliative surgical procedure was under- weight loss over the prior two months. eTh patient had no taken and included en bloc resection of the tumor with signicfi ant past medical history or any other symptomatology. a total gastrectomy/Roux-en-Y esophagojejunostomy, distal Computerized tomography (CT) imaging revealed a 14 cm pancreatectomy, splenectomy, left partial hepatectomy, and tumor with possible central necrosis that originated from extended right colectomy. the posterior gastric wall and extended superiorly to the diaphragm (Figure 1(a)). Additionally, there appeared to be metastases in the right pelvic cavity (5.5 cm) and within a 3.2. Histopathological Diagnosis and Genetic Analysis. The right inguinal hernia (4.5 cm). An endoscopic biopsy of the resection revealed a 10.4× 6.4×6.3 cmtumorarisingfromthe gastric lesion revealed a spindle cell neoplasm which was stomach and invading into the spleen and pancreas. eTh bulk strongly and diffusely immunoreactive for CD117, CD34, and of the tumor was composed of pleomorphic, eosinophilic DOG1. S-100 protein, smooth muscle actin, desmin, and polygonal cells with bizarre nuclei, abundant cytoplasm, and cyokeratin IHC were negative. The diagnosis of GIST was increased mitotic activity (up to 3 mitotic gur fi es per 50 rendered. eTh patient was initiated on imatinib 400 mg daily. high power elds) fi ( Figure 2(b)). Also observed were areas Initial molecular testing was negative for exon 9 or exon 11 of marked hyalinization, consistent with treatment eeff ct, Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) Figure 2: Tumor at the time of en bloc resection. Left panels showing H&E (a, b) and immunophenotype of spindle cell component (a, c, e, g, and i) and right panels showing rhabdomyosarcomatous component (b, d, f, h, and j) as follows: (c, d) c-kit IHC, 200x, (e, f) DOG1 IHC, 200x, (g, h) desmin IHC, 200x, and (i, j) myoD-1, 400x. 4 Case Reports in Oncological Medicine and focal areas (<5% of the lesion) of a spindle cell tumor Curiously, the initial biopsy in our case was negative reminiscent of his previously biopsied GIST (Figure 2(a)). for KIT and PDGFRA mutations. This possibly represents a false negative result as the tumor was initially objectively eTh pleomorphic tumor cells were strongly positive for responsive to therapy, and tumors have not previously been desmin and focally positive for myoD1 but negative for reported to gain a primary-type (exon 9 or 11) mutation upon myogen (Myf-4), CD117, CD34, and DOG1 IHC, suggesting progression. rhabdomyosarcomatous differentiation. Inversely, the spindle With regard to therapy, sunitinib and regorafenib are cell component was positive for CD117, DOG1, and CD34 and approved therapies in the second and third lines, respectively, negative for the RMS antigens by IHC (Figures 2(c)–2(j)). but both have demonstrated only limited success [11–13]. A diagnosis of a dedifferentiated GIST with rhabdomyosar- Novel adjunct therapies targeting protein products down- comatous differentiation was made. Molecular testing for stream of KIT, such as PI3-K and MAPK/MEK, have been KIT mutations was performed on the two distinct histologic suggested, but to date these therapies have not become areas and both revealed an exon 11 deletion KV558-559. widely accepted or available [14]. Insucffi ient data exists on No imatinib resistance mutations were detected in exon whether standard rhabdomyosarcoma treatments such as 13, 17, or 18. Additionally, multiple brot fi ic omental nod- dactinomycin, vincristine, and cyclophosphamide would be ules (up to 1.4 cm) were resected at this time. These were more beneficial than TKIs for patients with dedifferentiated morphologically consistent with GISTs with marked tumor GISTs. response to imatinib treatment. No rhabdomyosarcomatous dieff rentiation was seen in these separate tumors. eTh patient 5. Conclusions was reinitiated on imatinib 400 mg daily and has remained on that dose for the past 4 years with evidence of stable disease. In summary, we report a genetically unique case of rhab- domyosarcomatous dedifferentiation in a GIST following TKI therapy. Our case supports prior reports that these 4. Discussion tumors behave in an aggressive fashion with early recurrence To ourknowledge,only6casesofrhabdomyosarcomatous and resistance to TKI treatment. The molecular ndings fi dedifferentiation in GISTs have been reported following suggestthattheresistancetoTKItherapyintheseraretumors is driven more by alternative mechanisms than through treatment with TKIs [4, 5]. Heterologous differentiation of secondary Kit/PDGFRA mutations. Further study is needed the primary tumor (as opposed to the metastases) has only to clarify these mechanisms as well as determine optimal been reported in 1 other case. This is the rfi st report of the treatment strategies. exon 11 deletion KV558-559 in this clinical setting. The rare cases of dedifferentiated tumors have generally demonstrated a more aggressive clinical course, with recur- Conflict of Interests rence and metastases. This stands in contrast to primary eTh authors declare that they have no conflict of interests. GISTs with rhabdoid morphology, which, although also uncommon, have not demonstrated malignant behavior [6, References 9]. Based on the small number of previously reported cases, [1] C. L. Corless, J. A. Fletcher, and M. C. Heinrich, “Biology of dedifferentiated tumors, as in our case, demonstrate resis- gastrointestinal stromal tumors,” Journal of Clinical Oncology, tance to the currently available TKI therapy. Time to treat- vol. 22, no. 18, pp. 3813–3825, 2004. ment failure in these rare tumors with RMS dedifferentiation [2] M. Miettinen and J. Lasota, “Gastrointestinal stromal tumors: ranged from 10 to 24 months [4, 5]. Our patient had only 8 review on morphology, molecular pathology, prognosis, and months of stable disease following TKI therapy. differential diagnosis,” Archives of Pathology and Laboratory In general, when treatment failure occurs, a unique Medicine,vol.130,no. 10,pp. 1466–1478, 2006. [3] M. D´ıaz Delgado, A. Hernandez ´ Amate, S. Pereira Gallardo, pattern of disease progression follows, termed a “resistant S. Jaramillo, J. A. Virizuela Echaburu, and R. J. Gonzalez- ´ nodule.” These nodules are seen on imaging as new cen- Cam ´ pora, “Gastrointestinal stromal tumors: morphological, tral or peripheral areas of enhancement within preexisting immunohistochemical and molecular changes associated with responding lesions. eTh se imatinib “resistant nodules” appear kinase inhibitor therapy,” Pathology and Oncology Research,vol. in about 50% of patients aer ft two years of therapy and are 17,no. 3, pp.455–461,2011. frequently found to have novel mutations in KIT or PDGFR [4] B. Liegl, J. L. Hornick, C. R. Antonescu, C. L. Corless, and (that were not present in the primary tumor). These findings C. D. M. Fletcher, “Rhabdomyosarcomatous differentiation in support the hypothesis that “resistant nodules” arise through gastrointestinal stromal tumors aeft r tyrosine kinase inhibitor clonal evolution [10]. However, of the reported GISTs with therapy: a novel form of tumor progression,” The American RMS dedifferentiation, only 1 of 6 has shown secondary KIT Journal of Surgical Pathology,vol.33, no.2,pp. 218–226, 2009. or PDGFR mutations [4]. The remaining vfi e, as in our case, [5] S.Zheng,K.-E. Huang, J. Jia, X. Li,and D.-Y.Tao,“Rhab- have only shown primary-type exon 11 mutations. This has led domyosarcomatous differentiation in gastrointestinal stromal to the proposition that the dedieff rentiation may be related to tumors aer ft imatinib resistance: a potential diagnostic pitfall,” an alternative mechanism for TKI resistance, the genetic basis Experimental Biology and Medicine,vol.238,no. 1, pp.120–124, of which has yet to be established. 2013. Case Reports in Oncological Medicine 5 [6] I.-M. Schaefer, P. Strob ¨ el, S. Cameron et al., “Rhabdoid mor- phology in gastrointestinal stromal tumours (GISTs) is associ- ated with PDGFRA mutations but does not imply aggressive behaviour,” Histopathology,vol.64, no.3,pp. 421–430, 2014. [7] G.D.Demetri,M.VonMehren,C.D.Blankeetal.,“Efficacyand safety of imatinib mesylate in advanced gastrointestinal stromal tumors,” eTh New England Journal of Medicine ,vol.347,no.7,pp. 472–480, 2002. [8] M. van Glabbeke, “Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients,” Journal of Clinical Oncology,vol.28, no.7,pp. 1247–1253, 2010. [9] J.A.Hanson, J. C. Trent, D. Yang,and K. Cooper,“Small- intestinal rhabdoid gastrointestinal stromal tumor (GIST): mutation analysis and clinical implications of a rare morpho- logical variant,” International Journal of Surgical Pathology,vol. 19, no. 5, pp. 653–657, 2011. [10] J. Desai, S. Shankar, M. C. Heinrich et al., “Clonal evolution of resistance to imatinib in patients with metastatic gastrointesti- nal stromal tumors,” Clinical Cancer Research,vol.13, no.18, pp. 5398–5405, 2007. [11] G. D. Demetri, M. C. Heinrich, J. A. Fletcher et al., “Molecular target modulation, imaging, and clinical evaluation of gastroin- testinal stromal tumor patients treated with sunitinib malate aer ft imatinib failure,” Clinical Cancer Research,vol.15, no.18, pp. 5902–5909, 2009. [12] H. Joensuu, F. de Braud, P. Coco et al., “Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate,” Annals of Oncology,vol.19, no.1,pp. 173–177, 2008. [13] G. D. Demetri, P. Reichardt, Y.-K. Kang et al., “Effi cacy and safety of regorafenib for advanced gastrointestinal stromal tumours aeft r failure of imatinib and sunitinib (GRID): an inter- national, multicentre, randomised, placebo-controlled, phase 3 trial,” The Lancet , vol. 381, no. 9863, pp. 295–302, 2013. [14] C. R. Antonescu, “eTh GIST paradigm: lessons for other kinase- driven cancers,” The Journal of Pathology ,vol.223,no.2,pp.251– 261, 2011.

Journal

Case Reports in Oncological MedicinePubmed Central

Published: Jan 28, 2015

References