Pathology – Research and Practice 210 (2014) 264–266
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Pathology – Research and Practice
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eaching cases
edifferentiated gastrointestinal stromal tumor arising de novo fromhe small intestine
acqueline J. Choia, Laura Sinada-Bottrosa, Ajay V. Makerb, Elliot Weisenbergc,∗
University of Illinois at Chicago, Department of Pathology, Chicago, IL, USACreticos Cancer Center at Advocate Illinois Masonic Medical Center, Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago,hicago, IL, USAAdvocate Illinois Masonic Medical Center, Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
r t i c l e i n f o
rticle history:eceived 27 October 2013eceived in revised form7 November 2013ccepted 30 December 2013
a b s t r a c t
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointesti-nal tract and usually display monotonous cytologic features and immunoactivity for CD117. AnaplasticGIST, with pleomorphic cells and loss of CD117, until recently have only been reported in patients withchronic imatinib mesylate treatment. Dedifferentiated GISTs arising de novo is a newly identified entity
eywords:edifferentiatednaplastic
that may prove to be difficult to diagnose. We present the case of a 52-year-old female found to have adedifferentiated GIST without prior imatinib mesylate therapy. This case is the first reported dedifferen-tiated GIST arising de novo from the small bowel, and at 30 cm in greatest diameter, the largest reportedto date. Additionally, we demonstrate for the first time the loss of DOG1 in the anaplastic componentof the tumor. De novo dedifferentiated GIST is a rare and diagnostically challenging tumor that may be
Gastrointestinal stromal tumors (GISTs) are the most com-on mesenchymal tumors of the gastrointestinal (GI) tract and
sually display monotonous cytologic features with characteris-ic immunoactivity for CD117, the KIT oncoprotein [4,8,11]. Untilecently, anaplastic variants of GIST, with pleomorphic cells andoss of CD117 were only reported in patients who had undergonehronic treatment with a kinase inhibitor, such as imatinib mesy-ate [10,15]. The occurrence of dedifferentiated GIST arising de novos a newly identified entity that may prove to be exceedingly dif-cult to diagnose with a markedly anaplastic appearance and lackf CD117 expression.
We present the case of a 52-year-old female who was found toave a dedifferentiated GIST. It is the first reported dedifferentiatedIST arising de novo from the small bowel and the largest to date.
ase report
The patient is a 52-year-old obese (body mass index 40.3 kg/m2)emale who presented initially to an outside institution withubjective fevers, abdominal pain, non-bloody diarrhea and vague
∗ Corresponding author at: Department of Pathology, Advocate Illinois Masonicedical Center, 836 West Wellington Avenue, Chicago, IL 60657, USA.
symptoms of feeling unwell. She stated that she was a healthy,nonsmoking and active individual who recently had decreasedenergy and a smaller appetite. Her medical history is signifi-cant for hypertension and gastroesophageal reflux disease. At thetime, she was found to be anemic (hematocrit 20.9), and under-went a colonoscopy which demonstrated colitis and was newlydiagnosed with presumed ulcerative colitis and started on 5-ASAtherapy. Shortly after discharge, she presented to our institutionwith worsening symptoms and complaints of early satiety. Herphysical exam revealed a large, firm palpable mass in the centerof her abdomen and a computed tomography scan demonstrateda 19 cm × 18 cm × 15 cm, heterogenous, multiloculated cystic masswith soft tissue components that encased a loop of small bowelwithout obstruction and abutted the anterior abdominal wall[Fig. 1]. As lymphoma and GIST were in the differential and tissuebiopsy would affect management decisions, a fine needle aspira-tion and a core biopsy were performed under ultrasound guidanceat a location just under the midline fascia which showed an atypi-cal spindle cell proliferation suspicious for malignancy. The biopsystained focally positive for smooth muscle actin (SMA), and wasnegative for myogenin, pancytokeratin, panmelanoma, DOG1 andCD117. As a result, a tentative diagnosis of a malignant spindletumor was reported. A metastatic work up was negative.
The patient was severely deconditioned and malnourished
(albumin 1.7 g/dL, prealbumin 6.3 mg/dL), therefore surgicalresection was planned after improving her nutritional status. How-ever, the patient continued to have high fevers, acute abdominalpain and cramping not adequately controlled with pain medicine,
J.J. Choi et al. / Pathology – Research and Practice 210 (2014) 264–266 265
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ig. 1. Axial (left) and coronal sections (right) of a computed tomography scan reveanvolving multiple loops of small intestine, and surrounded by ascites.
nd ongoing GI blood loss requiring blood transfusions, therefore,nformed consent was obtained for an exploratory laparotomy andperative intervention.
Intraoperative exploration revealed a large, heavy, well vascu-arized and friable heterogenous mass filling the pelvis from theetroperitoneum to the anterior abdominal wall. It was fixed andensely adherent to the rectosigmoid and multiple loops of smallowel. The mass was carefully excised en-bloc with multiple loopsf small bowel, small bowel and transverse colon mesentery, theectosigmoid, the anterior peritoneum and a non-involved preaor-ic retroperitoneal fat plane. Continuity of the small bowel wase-established and given concern for biopsy positive ulcerativeolitis in the left colon, and the patient’s severe protein calorie mal-utrition and ascites, an end colostomy and Hartmann’s pouch waserformed.
The mass weighed 4.4 kg and measured0.0 cm × 21.0 cm × 9.5 cm. The majority of the tumor demon-trated necrosis and high mitotic activity (40/50 hpf). Afterxtensive sampling, there were two distinct morphologies presentn the tumor [Fig. 2a]. An estimated 2% showed a conventionalastrointestinal stromal tumor composed of bland spindled cells.he remainder of the lesion consisted of a cellular proliferationf anaplastic cells with an epithelioid morphology with openrregular nuclei and variably prominent nucleoli with very rare
reas suggesting heterologous differentiation [Fig. 2b]. Immuno-istochemistry demonstrated that the conventional componentas strongly immunoreactive for CD117, CD34 and DOG1, whereas
he adjacent dedifferentiated component lacked this staining pat-
ig. 2. (A) Dedifferentiated gastrointestinal stromal tumor (GIST) component on left. Conation. (B) Pleomorphic cells of dedifferentiated GIST component. Hemotoxylin and eosin
large dedifferentiated GIST filling the anterior–posterior diameter of the abdomen,
tern [Fig. 3]. Both components were negative for AE1+3, desmin,S100, HMB45, CD31, SMA, smooth muscle myosin and myogenin.The Ki-67 labelling index was an estimated 50%.
Molecular studies for the two distinct areas of tumor did notshow any activating mutations for the KIT gene on exons 9, 11,13, or 17. There were also no activating mutations detected for theplatelet derived growth factor alpha (PDGFRA) gene on exons 12 or18 in either component.
The tumor originated from a loop of jejunum and invaded intothe serosa of the adjacent loops of bowel, with ulcerations in themucosa as a source of bleeding. The margins were negative. Alllymph nodes were negative. Examination of the large intestineshowed no evidence of idiopathic inflammatory bowel disease.
Discussion
Gastrointestinal stromal tumors are rare tumors comprising anestimated 1% of all GI neoplasms [12], and yet are the most commonmesenchymal tumors of the gastrointestinal tract with estimated5000–6000 new cases per year in the United States [8]. They mostcommonly arise in the stomach, although may be present anywherein the digestive tract. They putatively originate from the interstitialcells of Cajal, which are pacemaker cells responsible for peristalsisin the gastrointestinal tract [4]. Typical GIST tumors are describedas having a monotonous morphology, with uniform, fusiform cells
with scant, fibrillary, eosinophilic cytoplasm in intersecting fasci-cles or short storiform patterns. A less common epithelioid varianthas also been well described, as well as mixed patterns, but they
ventional GIST component on right. Hemotoxylin and eosin stain at 40× magnifi- stain at 100× magnification.
266 J.J. Choi et al. / Pathology – Research and Practice 210 (2014) 264–266
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ig. 3. Immunohistochemical stains of dedifferentiated gastrointestinal stromal tuB) DOG1, and (C) CD34. 20× magnification.
sually appear morphologically bland with low mitotic activity.mmunohistochemical stains are nearly always necessary to con-rm the diagnosis. CD117, also known as c-kit, stains for a tyrosineinase receptor, found on a variety of cells including the interstitialells of Cajal [8,11]. A positive staining pattern infers an activat-ng mutation in the KIT proto-oncogene, most commonly locatedn exons 11 and 13 when present [6]. A less common activat-ng mutation may also be found on the PDGFRA proto-oncogene8,14]. 4–15% of GISTs are wild-type tumors and do not have aetectable KIT or PDGFRA mutation [8]. Rarely, GISTs have alsoeen reported to have BRAF mutations [1]. Five percent may arise
n the setting of syndromic diseases such as in Carney’s triad oreurofibromatosis type 1 (NF1) [2,7]. GISTs that arise from a non-IT mutation origin tend to have a more epithelioid morphologynd lack CD117 staining [14]. Proper identification of a GIST and itsutations is important because specific molecular therapy can be
argeted to tumors with KIT and PDGFR mutations with tyrosineinase inhibitors [3,12,14].
A relatively new stain, DOG1 has been shown to be also spe-ific and sensitive in the diagnosis of GIST, and particularly helpfuln CD117 negative tumors [13]. No previous studies have demon-trated its utility in dedifferentiated GISTs, and our case showed
loss of expression in the anaplastic component of the tumor. CD117 loss may also be coupled with a de novo expression ofytokeratin and desmin, although this has been variably reported6,10,13].
Dedifferentiated variants of GIST have only been reported in aandful of cases in the literature and have until recently, alwayseen associated with prolonged treatment with the tyrosine kinase
nhibitor imatinib mesylate [10,15]. It is thought that dedifferentia-ion is a morphological progression from the classic CD117 positiveIST to a CD117 negative tumor by KIT induced mechanism of resis-
ance to therapy [15]. Imatinib induces an apoptotic effect in GISTumors by reactivating the original KIT oncogene. In patients whoave had prolonged imatinib treatment, it has been theorized that aecond KIT mutation on the same allele can lead to treatment failure5,9]. However, it has recently been reported that not all dediffer-ntiated GISTs are associated with the acquisition of an additionalutation and suggests that genetic instability may be the culprit in
edifferentiated components [6]. This has been validated by fluo-escence in situ hybridization (FISH) analysis that such tumors mayemonstrate a loss of heterozygosity or low level amplification athe KIT locus [6].
In a recent multi-institutional study of these tumors, only fiverevious cases of dedifferentiated GISTs arising de novo were iden-ified [6]. Consistent with the case described here, each of the deovo GISTs demonstrated a dedifferentiated component arising
rom an adjacent conventional component. Each of these five casesad loss of CD117 and CD34 in their anaplastic component andhowed variable acquired expression of cytokeratin in three cases.
one of the de novo GISTs acquired desmin expression. Molecular
tudies demonstrated KIT mutations on exon 11 in three of the fiveases, with a 557-8WK deletion and two wild-type tumors.
[
IST) component on left and conventional GIST component on right for (A) CD117,
In conclusion, we expand upon the existing literature concern-ing dedifferentiated GISTs arising de novo without prior imatinibexposure. We demonstrate for the first time the loss of DOG1in the anaplastic component of the tumor, additionally, this caseis the first reported dedifferentiated GIST arising de novo fromthe small bowel, and at 30 cm in greatest diameter, the largestreported to date. The recent recognition of this entity presentsa significant challenge to the pathologist as it shows a markedlydifferent morphology from conventional GISTs and lacks the diag-nostic immunophenotype for CD117 and DOG1 that are used toconfirm the diagnosis. It is important to recognize these anaplasticcomponents may arise from a primary GIST without a prior his-tory of imatinib therapy. De novo dedifferentiated GIST is a rareand diagnostically challenging tumor that may be mischaracter-ized unless considered in the differential diagnosis. This case alsoillustrates the necessity of sufficient sampling to find both conven-tional and dedifferentiated components to properly identify it as adedifferentiated GIST.
References
[1] N.P. Agaram, G.C. Wong, T. Guo, et al., Novel V600E BRAF mutations inimatinib-naïve and imatinib-resistant gastrointestinal stromal tumors, GenesChromosomes Cancer 47 (2008) 853–859.
[2] J. Andersson, H. Sihto, J.M. Meis-Kindblom, et al., NF1-associated gastroin-testinal stromal tumors have unique clinical, phenotypic, and genotypiccharacteristics, Am. J. Surg. Pathol. 29 (9) (2005) 1170–1176.
[3] C.R. Antonescu, Targeted therapy of cancer: new roles for pathologists in iden-tifying GISTs and other sarcomas, Mod. Pathol. 21 (Suppl. 2) (2008) S31–S36.
[4] C.R. Antonescu, The GIST paradigm: lessons for other kinase-driven cancers, J.Pathol. 223 (2011) 251–261.
[5] C.R. Antonescu, P. Besmer, T. Cuo, et al., Acquired resistance to imatinib in gas-trointestinal stromal tumor occurs through secondary gene mutations, Clin.Cancer Res. 11 (2005) 4182–4190.
[6] C.R. Antonescu, S. Romeo, L. Zhang, et al., Dedifferentiation in gastrointestinalstromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall,Am. J. Surg. Pathol. 37 (March (3)) (2013) 385–392.
[7] J.A. Carney, Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenalparaganglioma (Carney Triad): natural history, adrenocortical component, andpossible familial occurrence, Mayo Clin. Proc. 74 (6) (1999) 543–552.
[9] M. Debiec-Rychter, J. Cools, H. Dumez, et al., Mechanisms of resistance to imat-inib mesylate in gastrointestinal stromal tumors and activity of the PKC412inhibitor against imatinib-resistant mutants, Gastroenterology 128 (2005)270–279.
11] H. Joensuu, Gastrointestinal stromal tumor (GIST), Ann. Oncol. 17 (Suppl. 10)(2006) x280–x286.
12] I. Judson, G. Demetri, Advances in the treatment of gastrointestinal stromaltumours, Ann. Oncol. 18 (Suppl. 10) (2007) x20–x24.
13] B. Liegl, J.L. Hornick, C.L. Corless, et al., Monoclonal antibody DOG1.1 showshigher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors,including unusual subtypes, Am. J. Surg. Pathol. 33 (2009) 437–446.
14] M. Miettinen, J. Lasota, Gastrointestinal stromal tumors: review on morphol-
Lab. Med. 130 (10) (2006) 1466–1478.15] P. Pauwels, M. Debiec-Rychter, M. Stul, et al., Changing phenotype of gas-
trointestinal stromal tumours under imatinib mesylate treatment: a potentialdiagnostic pitfall, Histopathology 47 (2005) 41–47.
