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Background: Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal neoplasm of the gastrointestinal tract. Mutations of KIT and platelet-derived growth factor receptor alpha have been well characterized in GISTs. Patients with KIT mutations are generally sensitive to treatment with tyrosine kinase inhibitors. However, some patients with GIST, while initially sensitive to TKIs, gain resistance in later stages of treatment. Heterologous rhabdomyomsarcomatous dedifferentiation of advanced GISTs after long-term imatinib mesylate (IM) therapy has been reported. In these cases, the underlying molecular mechanism of tumor progression and transformation is unclear. Case presentation: We report one such patient with rhabdomyosarcomatous dedifferentiation of a GIST without metastatic disease after brief 3-month therapy with IM. The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region. Molecular analysis identified the activating KIT exon 11 mutation in both regions, indicating a common origin for both phenotypes. Additionally, the dedifferentiated component contained two synonymous variants in platelet-derived growth factor receptor alpha and KIT. The increased number of synonymous variants in the rhabdomyosarcomatous region may reflect increased genetic instability of this tumor that may have resulted in the loss of CD117 expression in the dedifferentiated component. Conclusion: This study adds to the growing consensus that rhabdomyosarcomatous GIST progresses from a common GIST primary tumor. The role of IM in this progression is uncertain; however short duration of IM treatment in this study supports the hypothesis that rhabdomyosarcomatous GIST progression is not a consequence of IM therapy. Furthermore, we provide additional information supporting the observation that CD117 negative rhabdomyosarcomatous transformation maintains the activating KIT variant without KIT expression. Keywords: Gastrointestinal stromal tumor (GIST), Rhabdomyosarcomatous dedifferentiation, KIT, Imatinib (IM), Tyrosine kinase inhibitor (TKI) * Correspondence: firstname.lastname@example.org Presented, in part at the Pennsylvania Association of Pathologists (PAP)- Harrisburg, PA, April 2018. Li Li and Marian Khalili contributed equally to this work. Departments of Surgery, Drexel University College of Medicine, 245 N 15th Street, Suite 7150, Philadelphia, PA 19102, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. BMC Cancer (2019) 19:913 Page 2 of 8 Background mutations, clonal evolution, sub-clonal selection, and me- Gastrointestinal stromal tumors (GISTs) are the most tastasis [9–12]. Gene copy number abnormalities may also common primary mesenchymal neoplasm of the gastro- be found in TKI resistant/dedifferentiated GISTs . intestinal (GI) tract. There are approximately 5000 new Rarely, primary or metastatic GISTs undergo dediffer- cases of clinically significant GIST in the United States entiation after initiation of IM. Dedifferentiation has each year . Arising from the interstitial cells of Cajal been described in many tumors, and mostly develops de (“pacemaker cells”), GISTs most commonly occur within novo independent of treatment. To our knowledge, only the stomach and small intestine. Rare but aggressive seven published cases have shown heterologous rhabdo- GISTs present with numerous intraperitoneal/serosal- myosarcomatous dedifferentiation in advanced GISTs based nodules or liver metastasis. Prognostication de- after long term IM therapy (14–54 months) [2, 14, 15] pends highly on tumor biology and size . (Table 1). Due to the rarity of rhabdomyosarcomatous Gain-of-function mutations of KIT receptor tyrosine kin- dedifferentiation of GISTs, the underlying molecular ase (RTK) or homologous RTK, platelet-derived growth mechanism of tumor progression and transformation is factor receptor alpha (PDGFRA) drive neoplastic cell poorly understood. Our current study adds new molecu- growth. Approximately 80–85% of GISTs have activating lar findings to this rare entity. mutations in KIT or PDGFRA. As a result, overexpression of CD117 (KIT protein) is a relatively specific marker for Case presentation the diagnosis of GIST . Most frequently, KIT mutations Clinical history are found in exon 11 (66–71%), followed by exon 9 (13%), The patient is a 75-year-old African American man exon 13, and exon 17. CD117 immunoreactivity has im- with past medical history of hypertension, gout, and portant therapeutic implications as patients harboring KIT previous DVT. He initially presented to an outside in- mutations (exon 11) respond more effectively to TKI (ima- stitution with early satiety, increasing abdominal girth, tinib mesylate (IM) or sunitinib malate) treatment [3, 4]. and 20-pound weight loss. A well circumscribed mass, Definitive treatment of GIST remains surgical resec- 9.3 cm likely originating from the greater curvature of tion. However, in the IM era, medical management is the stomach, was seen on CT scan. Subsequently, he crucial in the neoadjuvant and adjuvant settings. Based underwent an endoscopy May 2017, revealing a on findings from the Z9001 trial, IM was approved by rounded, submucosal lesion. Biopsy of the lesion re- the FDA for intermediate-high risk GISTs as adjuvant vealed spindle to epithelioid proliferative neoplasm therapy, while many have endorsed its use preoperatively with focal necrosis. Tumor cells showed positive im- for potentially resectable lesions [5, 6]. Furthermore, pa- munoreactivity to CD117, CD34 and SMA (focal), but tients were found to have improved recurrence-free and were negative for S100. The proliferative index Ki-67 overall survival when maintained on adjuvant IM for up was approximately 20% and mitotic figures were to three years [7, 8]. greater than 5/50 high power fields. An in-frame dele- However, some patients who are initially responsive to tion of 6 nucleotides in exon 11 of the KIT gene was IM, develop resistance with prolonged treatment. Such re- identified by next-generation sequencing (NGS). Diag- sistance is frequently associated with tumor recurrence, nosis was consistent with GIST. He was started on new tumor growth, or metastasis, with mostly preserved imatinib mesylate, 400 mg daily for 3 months. He was morphologic and immunophenotypic features. Resistance then referred to our tertiary medical center for pos- to IM, likely a result of KIT reactivation, is associated with sible bloodless surgical intervention due to his status expansion of imatinib-insensitive KIT mutations, re-pro- as a Jehovah’s Witness, declining the use of potential liferation of focal nodular tumors, gain of secondary gene blood products. Table 1 Amino acid changes in Rhabdomyosarcomatous dedifferentiation of GIST as reported in the literature Morphology (dedifferentiated) Mutation Amino Acid Change Reference Rhabdomyosarcomatous 6 nt deletion KV558–559del and Trp557Phe our sample Rhabdomyosarcomatous 6 nt deletion KV558–559 Jiang 2015  Rhabdomyosarcomatous Missense V559D Zheng 2013  Rhabdomyosarcomatous Missense V559D Liegl 2009 case 1  Rhabdomyosarcomatous 18 nt deletion 556–574 del Liegl 2009 case 2  Rhabdomyosarcomatous Missense V559D Liegl 2009 case3  Rhabdomyosarcomatous 54 nt deletion 556–574 del Liegl 2009 case 4  Rhabdomyosarcomatous none PDGFRA exon 18 del Liegl 2009 case 5  a b Morphology: the morphologic findings of dedifferentiated component after TKIs treatment in the metastatic sites and non-metastatic sites including our case Li et al. BMC Cancer (2019) 19:913 Page 3 of 8 On repeat imaging (Fig. 1a and b), the tumor was found Gross and histological diagnosis to have increased in size. The gastric mass appeared ad- The surgical specimen was examined grossly and fixed herent to the proximal jejunum, with mass effect on the in 10% neutral formalin. The representative specimen was transverse mesocolon. The decision was made to proceed embedded in paraffin and submitted for permanent histo- with surgery in September of 2017. Intra-operatively, a 29 logical examination. Four-micron thick hematoxylin and cm friable mass extending from the stomach adherent to eosin (H&E) stained sections were prepared. Risk stratifi- the serosa of the proximal jejunum and eroding into the cation was performed according to the recent National transverse mesocolon was observed. The patient under- Comprehensive Cancer Network (NCCN) guidelines.  went en bloc resection including sleeve gastrectomy, prox- Immunohistochemical stains for CD117 (rabbit polyclonal imal small bowel resection, and left hemicolectomy. The A4502, Dako), CD34 (clone QBEnd/10, mouse monoclo- patient was subsequently discharged home after resolution nal, Ventana), DOG-1 (clone SP31, rabbit monoclonal, of a postoperative ileus. The patient was restarted on Ventana), Desmin (clone DE-R-11, mouse monoclonal, Imatinib at a dose of 400 mg daily post-operatively and Ventana), smooth muscle actin (SMA) (clone 1A4, mouse has since been well tolerated. He has no evidence of monoclonal, Ventana), and MyoD1 (clone EP21, mouse disease on repeat CT scan 20 months after the operation. monoclonal, Cell Marque) were performed. Immunostain for myoenin (MYF-4) was performed by Neogenomics. The resection specimen revealed a 29 × 17 × 5 cm cystic/ hemorrhagic lesion arising from the stomach and extend- ing into the retroperitoneum and transverse mesocolon with adherence to the proximal jejunum. No prominent nodular components were seen. Microscopic examination of the surgically resected tumor demonstrated extensive necrosis and hemorrhage. The viable tumor showed hypercellularity and an invasive growth pattern with spindle and epithelioid cells arranged in lobules. The majority of tumor cells were uniform with abundant eosinophilic cytoplasm, rare pleomorphic nuclear features, and occasional para-nuclear vacuoles (Fig. 2a). The epithelioid component of the tumor was positive for CD117 (Fig. 2c) and vimentin (Fig. 2g) but negative for DOG-1 (Fig. 2e), MyoD-1 (Fig. 2l), myogenin (Fig. 2k), des- min (not shown), and SMA (not shown) by immunohis- tochemical (IHC) stains. Interestingly, a small sarcomatoid component of the tumor (approximately 5–10%), abruptly adjacent to the classic GIST, showed rhabdomyosarcomatous differentiation, which revealed sheets of pleomorphic, large and bizarre rhabdoblasts with abundant eosinophilic material in the cytoplasm, irregular nuclei, prominent nucleoli, and increased mitotic activity (Figs. 2b, and 3). These sarcomatoid cells were diffusely and strongly positive for vimentin (Fig. 2h) and MyoD-1 (focally, cytoplasmic and nuclear stains, Fig. 2j), but negative for CD117 (Fig. 2d), DOG-1 (Fig. 2f), myogenin (Fig. 2l), desmin (not shown), and SMA (not shown) by IHC stains. Notably, there was a loss of CD117 expression in the dedifferentiated component of the tumor. Additionally, sarcomatoid tumor cells had higher mitotic activity by immunostain for proliferative index Ki-67 compared to adjacent classic GIST tumor cells (Fig. 3a, b). The diagnosis of transformation of GIST with rhabdomyosarcomatous dedifferentiation was made. The tumor was a locally advanced high-risk Fig. 1 CT-scan of Gastrointestinal Stromal Tumor (GIST) Prior to GIST with risk of progressive disease based on tumor Surgery: a axial, b coronal size, mitotic figures and the organ of origin Li et al. BMC Cancer (2019) 19:913 Page 4 of 8 Fig. 3 H&E Stain Depicting Abrupt Transition of Epithelioid and Dedifferentiated (rhabdymyosarcomatous) Components of GIST: epithelioid component (Left) and dedifferentiated Fig. 2 Morphologic and Immunophenotypic Features of Epithelioid and (rhabdomyosarcomatous) (right) components of GIST at 100X Rhabdomyosarcomatous Components of Tumor: left panel reveals H&E magnification (a). Mitotic activity at abrupt transition area shown by (400X) (a) and immunohistochemical stains of CD117, DOG-1, vimentin, immunohistochemical stain for proliferative index Ki-67 at 50X MyoD1 and Myogenin- 200X (c, e, g, i, k) of the epithelioid cell magnification (b) components. Right panel reveals component H&E- 400X (b)and immunohistochemical stains of CD117, DOG-1, vimentin, MyoD1 and Myogenin (200X) (d, f, h, j, l) of the rhabdomyosarcomatous components Next-generation sequencing (NGS) analysis The two different tumor types were identified on an H&E slide and the different tumor types were manually macro- dissected from unstained slides. DNA was isolated using (stomach). Only small areas of fibrotic change were the QIAamp DSP DNA isolation kit (Qiagen, Inc). The present within the tumor, likely indicating minimal DNA was converted into a sequencing library using the therapeutic response to IM. Mitotic rate was high (38 Illumina TruSight Tumor-26 (TST26) gene library con- per 50 high power fields) in the transformed sar- struction kit and sequenced using the MiSeq sequencing comatoid component (Fig. 3b). The resection margins system (Illumina), following the manufacturer’sinstruc- were all negative. Twenty lymph nodes were negative tions. The sequence was compiled and aligned using the for tumor metastasis. The pathologic stage of this MiSeq Reporter v2.6.2 and the variant call file was read tumor was stage IIIB (pT4, PN0). Efficacy of treat- and annotated using VariantStudio v.3.0 (Illumina). ment was difficult to evaluate due to the nature of Genes (exons) analyzed include the following [Gene the lesion showing hyper- and hypo-cellularity, myx- (exon)]: AKT1 (2), ALK (23), APC (15), BRAF (11,15), oid stroma, fibrosis, and necrosis which is often seen CDH1 (8, 9, 12), CTNNB1 (2), EGFR (18–21), ERBB2 in untreated GISTs as well. 90–95% of the tumor spe- (20), FBXW7 (7–10,11), FGFR2 (6), FOXL2 (1), GNAQ cimen was viable. (4–6), GNAS (6,8), KIT (9,11,13,17,18), KRAS (2–5), Li et al. BMC Cancer (2019) 19:913 Page 5 of 8 MAP 2 K1(2), MET (1,4,13-18,20), MSH6 (5), NRAS (2–5), frequency, 25.42% vs. 4.57%) genes (Table 1). This indi- PDGFRA (11,13,17), PIK3CA (1,2,7,9,20), PTEN (1–7,9), cates that there are at least two unique populations of cells SMAD4 (8,11), SRC (10), STK11 (1,4,6,8), TP53 (2–5,7,8, present within this tumor. No variants were detected in 10,11). Analytical sensitivity was 5%. Human Genome Ver- the EGFR, NRAS, KRAS and BRAF genes; all of which sion (Human hg19) was used for molecular data analysis. have been previously reported to occur in dedifferentiated Next-generation sequencing of the endoscopic biopsy GISTs [2, 14, 15, 17]. specimen from an outside hospital showed an in-frame deletion of 6 nucleotides in exon 11 of KIT, with a vari- Cytogenetic analysis ant allele frequency of 51%. This finding represents the Karyotype analysis was submitted to the cytogenetics classic component of GIST (prior to patient receiving and molecular lab at St Christopher Children’s Hospital IM treatment). (Philadelphia, PA). The surgically resected tissue was evaluated in order Cytogenetic testing showed a complex male karyotype to investigate molecular differences between the classic 55~84 < 3n>,XY,+X,-1,+ 2,+ 3,-7,+ 8,+ 8,+ 9,+ 11,-12,+ 12,- and rhabdomyosarcomatous dedifferentiated compo- 13,-14,-15,+ 15,-16,-17,-18,-19,-19,-20,+ 20,+ 21. Previous nents of the GIST. Adjacent tissue from abrupt transi- studies have also showed complex karyotypes in dedif- tion areas (Fig. 3a, right) were macrodissected and ferentiated rhabdomyoblastic components of GIST . subjected to NGS using the TST26 gene panel (Illu- Previous studies have also shown the complex karyotype: mina). The variants identified are shown in Table 2. 54–55, XY, +Y, + 1, del (1)(p21), + 6, + 7, + 7, + 12, _14, Similar to the endoscopic biopsy specimen, NGS of the add (16), (p13), + 20, + 21, + 21[cp7]/46, XY . surgical specimen showed a KIT gene exon 11 in-frame deletion (a kinase activating variant) at relatively high levels in both the classic and dedifferentiated components. This Discussion and conclusion variant is a 6-nucleotide exon 11 in-frame deletion (NM_ Approximately 80–85% of GISTs possess activating mu- 000222.2:c.1670_1675delGGAAGG: p.W557_V559delinsF) tations of KIT, while 10% have activating mutations of of the KIT gene. This in-frame deletion removes amino PDGFRA. KIT and PDGFRA mutations are mutually ex- acids 558 and 559 and changes the amino acid at position clusive . GIST with a KIT (exon 11) mutation is 557 from a tryptophan to a phenylalanine. Comparison of more susceptible to IM therapy. Acquired mutations in the sequence variants in the classic GIST vs. dedifferen- KIT exons 13, 14, and 17 as well as PDGFRA exon 18 tiated GIST revealed no significant differences in nonsy- have been reported with long-term IM exposure . nonymous DNA variants. Four synonymous variants in Activating mutations in the BRAF (V600E) gene have PDGRFA, APC, EGFR, and MET, as well as a missense been identified in 7% of KIT/PDGFRA wild-type GISTs variant in TP53 were detected at similar levels in both located in the small intestine . GIST subtypes. No TKI resistant mutations were detected Studies have shown the morphologic and immunopheno- in exon 13, 17, or 18 of KIT or PDGFRA genes. typic changes with IM treatment of GISTs. “Resistant nod- However, the dedifferentiated component of our speci- ules” within response areas have been described on imaging men harbored two unique synonymous (silent) sequence in patients with treatment failure . Furthermore, variants when compared to the classic component. The morphologically, spindle shaped tumor cells become epi- unique synonymous variants are in the KIT (variant allele thelioid with variable CD117 expression . Although frequency, 25.99% vs. 4.21%) and PDGFRA (variant allele less common, anaplastic or rhabdomyosarcomatous Table 2 Variants identified in Classic and Rhabdomyosarcomatous (Rhabdo) GIST components Gene Nucleotide Change Amino Acid Change Consequence VAF Classic GIST VAF Rhabdo GIST KIT NM_000222.2:c.1670_1675delGGAAGG (6 nt) Trp557_Val559delinsPhe Inframe deletion 91.1 50.7 TP53 NM_000546.5:c.215C > G Pro72Arg missense 43 54.7 PDGFRA NM_006206.4:c.2472C > T none synonymous 4.6 (ND) 25.4 KIT NM_000222.2:c.2586G > C none synonymous 4.2 (ND) 26.0 PDGFRA NM_006206.4:c.1701A > G none synonymous 99.8 99.8 APC NM_000038.5:c.4479G > A none synonymous 51.2 49.9 EGFR NM_005228.3:c.2361G > A none synonymous 93.8 70.8 MET NM_001127500.1:c.1131C > T none synonymous 99.6 99.5 Gene, nucleotide change, amino acid change, consequence and variant allele frequencies (VAF) are shown. ND Not detected. The limit of detection for this assay is 5%, so VAFs below this threshold are not presented Li et al. BMC Cancer (2019) 19:913 Page 6 of 8 differentiation has also been seen with prolonged IM Even though the same KIT mutation genotype was found therapy [2, 14, 15, 17, 20, 21]. in both classic and rhabdomyosarcomatous components The dramatic morphologic and immunophenotypic of our patient’s GIST, de novo dedifferentiated GIST can- changes seen in the reported seven cases with rhabdo- not be excluded since he received short-term IM treat- myosarcoma involved abrupt transformation from classic ment for only 3 months. CD117-positive tumor cells to CD117-negative tumor Seven cases published in the literature have shown cells with marked anaplasia/pleomorphism [2, 14, 15, tumor progression to anaplastic dedifferentiation after at 17] (Table 1). Interestingly, of the seven cases reported, least 8-month TKI treatment (400 mg QD or more all but one showed KIT exon 11 mutations/deletions in doses) [2, 15, 17]. Similar to our case, Jiang’s case study both classic and dedifferentiated components of GIST also showed heterologous differentiation of the primary suggesting the common origin of these two components tumor (as opposed to metastases) following 8-month of [2, 14, 15, 17]. In one case, an exon 18 PDGFRA muta- TKI treatment . These findings support the hypoth- tion was present . In six of the seven cases, no add- esis that “resistant nodules” arise via clonal evolution itional mutations were identified in the IM resistant/ . Both our reported case and Jiang’s case demon- dedifferentiated tumor areas including KIT, PDGFRA, strate that tumor dedifferentiation following a short- KRAS, and BRAF [2, 14, 15, 17]. One case showed gain of term IM treatment course may be related to an alterna- KIT exon 13 mutation; however, this unusual differenti- tive mechanism of TKI resistance. This molecular mech- ation did not show specific molecular changes . This anism has not been established yet. raises the possibility of activation of KIT-independent Molecular analysis of our patient’s GIST revealed novel pathway contributing to loss of CD117. equivalent genotypes in both the classic and dedifferen- Rhabdomyosarcomatous dedifferentiation of GIST has tiated components, indicating a common origin rather been reported in metastatic lesions of the omentum, than a collision tumor (an important differentiation in ovary, peritoneum, mesentery and liver in patients with pathology practice) [15, 20]. Therefore, KIT mutational rapidly progressive IM-resistant metastatic disease. In all analysis is critical for accurate diagnosis of new lesions previously reported cases (7 cases), this sarcomatous de- not expressing KIT or showing unforeseen immunohis- differentiation occurred after therapy with TKI with or tochemical profiles and morphologic features. without surgical debulking exclusively in the setting of As in our case, in all seven reported cases of rhabdo- metastatic disease. To our knowledge, we are presenting myosarcomatous transformation of GIST, the prevalence the first case of rhabdomyosarcomatous dedifferentiation of KIT (exon 11) and PDGFRA activating mutations was in the absence of metastatic disease. preserved in each tumor’s dedifferentiated component. Interestingly, all reported cases of rhabdomyosarcoma- However, KIT protein expression (CD117) was either tous dedifferentiation (7 cases), as well as our case, re- completely lost (7 cases) or significantly reduced (1 case) veal complete loss of CD117 immunoreactivity and with transformation [2, 22]. Interestingly, all of these pa- preservation of the primary KIT gene exon 11 mutation tients were maintained on TKI, with variable responses to or deletion [2, 14, 15]. Broadly, the mechanism of dedif- therapy ranging from partial to complete (one patient). ferentiation in tumors (occurring de novo) may involve Some were continued on IM while others were transi- secondary genetic changes contributing to tumor progres- tioned to sunitinib for disease progression or lack of re- sion and transformation, accompanied by morphologic sponse to IM. When possible, surgical debulking was and immunophenotypic changes. In advanced GISTs, performed. In our patient with non-metastatic disease, morphologic and immunophenotypic changes do not complete surgical resection was performed. There were always elucidate diagnosis, particularly when evaluating no TKI resistance mutations in the R0 resected tumor; new lesions arising during treatment. However, molecular therefore, IM therapy was initiated with planned mainten- analysis of KIT mutations helps delineate the common ance for 3 years with periodic surveillance imaging. origin of these lesions, providing a link between the pri- Notably, in our patient, two synonymous (silent) vari- mary tumor and recurrence/metastases [2, 14, 15]. ants were found in the dedifferentiated GIST. Thus, two Antonescu et al, presented eight cases of GIST with ana- unique populations of cells may be present within the sar- plastic dedifferentiation (non-rhabdomyomatous) and a comatoid component. The low-level detection of these CD117-negative phenotype. Five of the patients had no two variants in the classic GIST component likely reflects prior history of IM exposure, whereas three of the patients contamination of the classic GIST component with dedif- received long-term IM therapy. Treatment with IM can ferentiated GIST cells during macrodissection. Variants lead to altered morphology and loss of CD117 reactivity with frequencies below 5% are typically not reported as (as seen in three of the eight patients). Only in tumors of present in the specimen. These unique silent variants may the three patients treated with IM did both classic and an- reflect a higher DNA replication error rate and/or genetic aplastic components have a KIT mutation genotype . instability in the dedifferentiated GIST. This is consistent Li et al. BMC Cancer (2019) 19:913 Page 7 of 8 with other studies that suggest that genetic instability, in- rhabdomyosarcomatous GIST progression is not a con- cluding loss of heterozygosity (LOH) and low level ampli- sequence of IM therapy. fication of KIT contribute to CD117-negative GISTs . In summary, our study shows morphologic and immu- Similarly, gene copy number abnormalities have been re- nophenotypic rhabdomyosarcomatous dedifferentiation of ported as the most common finding in dedifferentiated a treatment refractory GIST without metastasis after short- GISTs . It is important to note that the TST26 library term IM therapy. Together with reported cases, awareness kit only analyzes a limited number of exons from 26 of this rare clinical entity and its potential occurrence fol- genes, so it is possible that there are other unidentified lowing TKI treatment could prevent a diagnostic pitfall. unique variants, synonymous and nonsynonymous, in Molecular analysis provides valuable information exploring dedifferentiated GIST. Overall, this data suggests that ded- tumor origin and tumor progression and may assist with ifferentiated GIST contains an increased number of DNA optimal treatment strategies in the future. variants, as compared to classic GIST. Abbreviations Although the abrupt transition from CD117-positive GI: Gastrointestinal; GIST: Gastrointestinal stromal tumor; H&E: Hematoxylin epithelioid to CD117-negative rhabdomyosarcomatous and eosin; Human hg19: Human Genome Version; IM: Imatinib mesylate; LOH: Loss of heterozygosity; MYF-4: Myoenin; NCCN: National dedifferentiation is striking, the underlying molecular Comprehensive Cancer Network; NGS: Next gen sequencing; mechanism remains uncertain. The KIT activating vari- PDGFRA: Platelet-derived growth factor receptor alpha; RTK: Receptor ant is common in tumor cells in both the rhabdomyo- tyrosine kinase; SMA: Smooth muscle actin; TKIs: Tyrosine kinase inhibitors; TST26: Illumina TruSight Tumor-26 sarcomatous and classic GIST regions of the tumor, which strongly indicates that both components origi- Acknowledgements nated from the same primary tumor cell. Therefore, the Not applicable. loss of KIT expression is likely due to additional genetic Authors’ contributions or epigenetic changes that arose during rhabdomyosar- MK, LL, GJ, PB, WFM, and WBB contributed to the writing of the manuscript. comatous progression. MK, LL GH, PB, WFM, WBB, MS, and JSH authors contributed to analysis of the patient’s data/findings. All authors edited the final manuscript. All In addition to gross chromosomal rearrangements, po- authors read and approved the final manuscript. tential alterations could include mutations and/or small insertions/deletions that disrupt the open reading frame Funding Not applicable (no funding received). of the KIT gene or the splicing and processing of the KIT mRNA. Additionally, mutations within the KIT pro- Availability of data and materials moter may prevent transcription of the gene, preventing Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. KIT protein expression. These theoretical DNA variants would be beyond the coverage of the NGS used in this Ethics approval and consent to participate study and thus not detected. Conversely, epigenetic Not applicable. changes, such as promoter methylation, could be re- Consent for publication sponsible for the loss of kit expression in the rhabdo- Consent for publication was obtained from the patient and all co-authors. myosarcomatous tumor by blocking transcription of the Written informed consent obtained from the patient. KIT gene. In addition to the TP53 missense mutation, Competing interests there were 4 synonymous variants (APC, MET, EGFR, The authors declare that they have no competing interests. and PDGFRA) that were present in both GIST pheno- types (Table 1) at similar variant allele frequencies. Author details Department of Pathology and Laboratory Medicine, Drexel University These likely represent germline variants, but this can College of Medicine, 245 N. 15th Street, Philadelphia, PA 19102, USA. only be confirmed by testing normal tissue from the pa- Departments of Surgery, Drexel University College of Medicine, 245 N 15th tient. Secondary BRAF and/or KRAS mutations have Street, Suite 7150, Philadelphia, PA 19102, USA. Department of Hematology and Oncology, Drexel University College of Medicine, 245 N. 15th Street, been found coexisting with KIT or PDGFRA mutations Philadelphia, PA 19102, USA. in naive GIST, but their significance in inducing GIST dedifferentiation is unclear. No BRAF and KRAS muta- Received: 24 April 2019 Accepted: 23 August 2019 tions were seen in our patient . Additionally, there were no mutations of KIT exons 13, 14, and 17 as well References as PDGFRA exon 18, which have been reported after 1. 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BMC Cancer – Springer Journals
Published: Sep 13, 2019
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