Arab Journal of Gastroenterology 10 (2009) 151–154

Contents lists available at ScienceDirect

Arab Journal of Gastroenterology

journal homepage: www.elsevier .com/ locate/a jg

Case Report

Metastatic gastrointestinal stromal tumours of the stomach: A report on twocases and literature review

Gaurav Aggarwal *, Arvind Diwakar, Bhaskar Satsangi, Devendra K. Jain, Parvinder Lubana,Sonia Moses, Raj K. MathurDepartment of Surgery, M.G.M. Medical College & M.Y.H. Group of Hospitals, Indore, Madhya Pradesh 452 001, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 7 October 2009Accepted 19 October 2009

Keywords:Gastrointestinal stromal tumourLymph node metastasesImatinibc-Kit

1687-1979/$ - see front matter � 2009 Arab Journal odoi:10.1016/j.ajg.2009.10.005

* Corresponding author. Tel.: +91 09993298129.E-mail address: drgaurav1981@rediffmail.com (G.

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours of the gastrointestinal tract,accounting for approximately 1% of gastric malignancies. We report on two cases of large malignant irre-sectable stromal tumours of the stomach with presence of concomitant distant metastases, treated pal-liatively, and followed by adjuvant imatinib therapy. The rarity lies in the presence of distant as well aslymph node metastases. The literature on this topic is reviewed.

� 2009 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction An exploratory laparotomy was done. Intraoperatively, a large

Gastrointestinal stromal tumours are mesenchymal tumours ofthe gastrointestinal tract, accounting for approximately 0.2–1%[1,2] of gastric malignancies. Primary GISTs can originate from allregions of the gastrointestinal tract most commonly being foundin the stomach (40–70%), small bowel (20–40%), colorectum (5–15%) and oesophagus (5%) [10]. We report on two cases of largemalignant irresectable stromal tumours of the stomach with pres-ence of concomitant distant metastases, treated palliatively, andfollowed by adjuvant imatinib therapy.

Case report

Case 1: a 48 year old male presented to the surgery departmentof our hospital with vague abdominal pain and a large lump occu-pying the entire left abdomen. Clinically, a large lobulated lesionwas palpable in the upper abdomen, about 22 � 19 � 15 cm, pre-dominantly involving the left upper half, and appearing to extendup to the pelvic inlet. Ultrasonography showed a heterogeneousmass with a size of 16 � 14 � 12 cm, with cystic necrotic compo-nents interspersed. A CT scan confirmed the presence of a11 � 6 cm mass occupying the left upper abdomen (Figs. 1 and2). Upper gastrointestinal endoscopy revealed a large globularulcerated lesion with central umbilication at the posterior wall ofthe body of the stomach. Ultrasound guided biopsy was doneand a gastrointestinal stromal tumour was diagnosed.

f Gastroenterology. Published by El

Aggarwal).

cystic lesion 25 � 18 cm in size, occupying the lesser sac, denselyadherent to the posterior wall of the stomach and transverse colonand extending downward up to pelvic inlet was present (Fig. 3).Furthermore, perigastric lymph nodes were also found to be in-volved. Intratumoural evacuation of haemorrhagic, necrotic mate-rial with intralesional drain placement in the lesser sac as well aslymph node biopsy was done and specimen sent for histopathology.

Microscopy showed elongated spindle like cells with hyper-chromatic nuclei and areas with a whorled pattern, while the cystwall showed fibrofatty tissue with smooth muscle bundles infil-trated with dense round cells. GIST of the stomach was diagnosedbased on these findings. Postoperative period was uneventful andpatient was started imatinab mesylate therapy.

Case 2: a 36 year female presented to us with anaemia and alump in her left upper abdomen. Ultrasound was done and itshowed a heterogenous mass 10 � 8 � 8 cm in size with cystic ne-crotic components interspersed. Upper gastrointestinal endoscopyrevealed an antral tumour confined to the submucosa. CT scan wasfurther done and showed a 10 cm intramural mass and multiple li-ver metastases. A concomitant CT guided biopsy was done and itastoundingly diagnosed a GIST of the stomach.

The patient was managed conservatively and subsequently dis-charged on lifelong therapy of imatinib mesylate.

Discussion

Gastrointestinal stromal tumours (GISTs) are the most commonsarcomas of the gastrointestinal tract, accounting for 0.2% of allgastrointestinal tumours [1,2]. The term GIST was first used by

sevier B.V. All rights reserved.

Fig. 3. Intraoperative photograph with the marker showing the mass at theposterior stomach wall.

Fig. 1. Sagittal view of the abdominal CT scan showing the mass occupying the leftupper abdomen.

Fig. 2. Coronal section of the CT scan with the dimensions of the mass clearlystated.

152 G. Aggarwal et al. / Arab Journal of Gastroenterology 10 (2009) 151–154

Mazur and Clarke in 1983 to describe the nonepithelial tumours ofthe gastrointestinal tract lacking the ultrastructural feature ofsmooth muscle cells as well as the immunohistochemical charac-teristics of schwann’s cells [3]. Based on their histologic and immu-nohistochemical features, GIST are presumed to originate from theinterstitial cells of Cajal (ICC), which are components of the intes-tinal autonomic nervous system and act as pacemakers, regulatingintestinal peristalsis [4].

In 1998, Hirota et al. demonstrated the involvement of a func-tional mutation of the kit proto-oncogene [5]. Kit is a tyrosine ki-nase receptor that gets activated when bound to a ligand knownas ‘steel factor’ [6]. Oncogenic mutations of kit have been foundin neoplasms associated with mast cell tumours, myelofibrosis,germ cell tumours, GIST, etc. [7]. GISTs are identified by the univer-sal expression of the CD 117 antigen (95%) [7]. They have beenfound to be associated with functional mutations in the PDGFRAtyrosine kinase receptor [8]. Furthermore, transition from ICChyperplasia to low risk GIST is associated with 14q deletion, whileloss of 22q is found in high risk or metastatic GIST [9]. The broadmorphological spectrum exhibited by GISTs at a light microscopicand ultrastructural level has generated much debate and contro-versy concerning tumour histogenesis. Although this will probablyremain for the foreseeable future, Kindblom et al. [4] and more re-cently Sircar et al. [10] have elegantly provided considerable sup-port for a possible histogenetic origin from the ICCs encounteredin the gastrointestinal tract, which are thought to play a role incoordinating intestinal motility [11,12]. The ICCs appear to bemodified smooth muscle cells occurring at various intramural siteswithin the intestinal tract, primarily in the muscularis propria andin association with the myenteric plexus.

Sites outside gastrointestinal tract that express CD 117/c-kit aremelanocytes, basal cells of epidermis, immature Langerhans cellsin the epidermis, variety of epithelial cells (breast/salivary gland/sweat gland/renal tubule), cells present in the reproductive system,a subset of glial cells and osteoclast precursor.

Although CD 117 is a diagnostically useful antigen expressed bythe ICC (and in most GISTs), it is important to be aware of theexpression of this antigen in a variety of other cells.

Primary GIST can originate from all regions of the gastrointesti-nal tract but are most commonly found in the stomach (40–70%),small intestine (20–40%), colorectum (5–15%) and oesophagus(5%) [13]. They are equally common in men and women and usu-ally present in the 40–60 age group [14]. Association of paragan-gliomas, pulmonary chondromas, and gastric lesions, known as

Fig. 5. Spindle cell variety of GIST on histopathology.

G. Aggarwal et al. / Arab Journal of Gastroenterology 10 (2009) 151–154 153

‘Carney’s triad’, was initially classified as leiomyosarcoma [15].Many GISTs are asymptomatic discovered incidentally duringimaging and laparotomy for other reasons. In advanced diseases,patient may present with a mass lesion or with vague abdominaldiscomfort, although the tumour can grow to a very large size be-fore producing any symptoms. GISTs can be highly vascular andbleeding is one of the most common symptoms. These tumoursare typically soft and friable and can cause life threatening haem-orrhage. Tumour rupture along with intraperitoneal bleeding canoccur, leading to a high risk of dissemination by peritoneal seedingof the tumour. Obstruction of the gastrointestinal tract is occasion-ally a condition at presentation and can lead to perforation. GISTswith overt metastatic diseases account for 5–15% of all cases[13,16]. The most common metastatic sites are the liver andperitoneum. Diffuse peritoneal spread is not uncommon and mayinvolve innumerable small tumour nodules replacing the omen-tum, studding the diaphragmatic surface or covering the serosalsurface of the bowel.

GISTs, gastrointestinal leiomyoma or leiomyosarcoma, schwan-noma, local extension by a primary retroperitoneal dedifferentiat-ed liposarcoma, benign and malignant vascular tumours, intra-abdominal fibromatosis (desmoid tumour), carcinoid with aspindle cell morphology ST and metastatic disease (spindle cellmelanoma/spindle cell carcinoma) are the predominant tumoursthat may need to be considered in the differential diagnosis. Mostof these tumours can be characterised accurately on the basis ofprecise clinical data and diligent microscopy, supplemented byappropriate immunohistochemical, ultrastructural, and molecularbiological analyses. Differentiating GISTs from true smooth muscletumours is clinically relevant because of differences in biologicalbehaviour and can sometimes be difficult.

They cannot be easily differentiated from other GI tumours ofsmooth muscle origin (Figs. 4 and 5), however, because of theirsubmucosal location. Fine needle aspiration or core biopsy withendoscopic ultrasound guidance is commonly required to obtaintissue for diagnosis [17]. CT scans are used to determine the ana-tomic extent of the GIST and to assist with operative planning.Unfortunately, CT is unable to differentiate between inflammatoryadhesions and malignant involvement of an adjoining organ, and isunlikely to identify any peritoneal metastasis smaller than 2 cm indiameter. PET scan is useful along with CT for evaluating GIST intotality as well as for assessing response to chemotherapy. Sequen-tial scans prior to and after imatinib mesylate reliably and rapidlyindicate the responsiveness or resistance of the tumour to therapy[18].

GIST exhibits a wide spectrum of clinical behaviour. It may re-main stable for years. Primary tumours more than 5 cm and thosewith increased mitotic activity are associated with poor prognosis.

Fig. 4. Epitheloid variety of GIST on histopathology.

Location of the tumour in the small bowel further worsens the out-come [1,19].

Surgery remains the gold standard therapy for all resectable tu-mours. The importance of clear resection of margins should beemphasized. Tumour rupture or any trauma to the pseudocapsuleis associated with an enormously increased risk of recurrence,including a risk of dissemination of tumour throughout the perito-neum. If lesions involve adjacent organs, en bloc resection must bedone in order to avoid further spillage. Overall 5 year survival ratesafter complete resection of localised GIST are 40–55% [20–23].Lymph node metastases are extremely rare so that regional lym-phadenectomy is not recommended routinely. Lymph node dissec-tion should be undertaken for patients with any evidence orsuspicion of nodal metastasis.

The typical site of tumour recurrence following resection ofGIST is the liver and peritoneum. Pulmonary metastases are rare.Mostly abdominal/pelvic CT scans are used for post treatment fol-low up.

Although it is not well documented which group of patients willbenefit most from imatinib treatment as well as the duration oftreatment, its success as an orally administered inhibitor of thekit receptor tyrosine kinase in managing metastatic disease haslead to an improvement of resectability, especially in cases of tech-nically inoperable primary tumours. Responses to imatinib are evi-dent in 30–40% of patients after 7 months and 50–60% after9 months of treatment [24]. Surgery is performed when tumoursize has decreased to the point at which resection is technicallypossible or when successive CT scans show no further evidenceof tumour shrinkage.

In conclusion, GISTs are the most common mesenchymal neo-plasms of the stomach and small intestine and are relatively lessfrequent at other gastrointestinal sites. A lack of awareness of theirbroad morphological spectrum can complicate diagnosis. Never-theless, an increasing awareness of their immunophenotypic,ultrastructural, and genotypic features coupled with an evolvingunderstanding of their histogenesis is facilitating our ability toidentify these tumours. Surgery remains the gold standard fortreatment of patients with resectable, localised gastrointestinalstromal tumours. On the contrary, palliation along with imatinibforms the mainstay in managing the converse. Due to the rarityof lymph node metastases, lymph node dissection should beundertaken only in case of evidence or suspicion of nodal involve-ment. A guarded approach is, thus, vital in the appropriate as wellas timely management and satisfactory outcome of such patients.

References

[1] Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromaltumors: a consensus approach. Hum Pathol 2002;33(5):459–65.

[2] Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin2005;55(1):10–30.

154 G. Aggarwal et al. / Arab Journal of Gastroenterology 10 (2009) 151–154

[3] Mazur MT, Clark HB. Gastric stromal tumors. Reappraisal of histogenesis. Am JSurg Pathol 1983;7(6):507–19.

[4] Kindblom LG, Remotti HE, Aldenborg F, et al. Gastrointestinal pacemaker celltumor (GIPACT): gastrointestinal stromal tumors show phenotypiccharacteristics of the interstitial cells of Cajal. Am J Pathol 1998;152(5):1259–69.

[5] Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations ofc-kit in human gastrointestinal stromal tumors. Science 1998;279(5350):577–80.

[6] Fleischman RA. From white spots to stem cells: the role of the kit receptor inmammalian development. Trends Genet 1993;9(8):285–90.

[7] Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature ofgastrointestinal stromal tumors. Cancer Res 2001;61(22):8118–21.

[8] Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations ingastrointestinal stromal tumors. Science 2003;299(5607):708–10.

[9] Corless C, Fletcher J, Heinrich M. Biology of gastrointestinal tumors. J ClinOncol 2004;22:3813–25.

[10] Sircar K, Hewlett BR, Huizinga JD, et al. Interstitial cells of Cajal as precursors ofgastrointestinal stromal tumors. Am J Surg Pathol 1999;23(4):377–89.

[11] Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells? Adv AnatEmbryol Cell Biol 1982;71:1–130.

[12] Hagger R, Finlayson C, Jeffrey I, et al. Role of the interstitial cells of Cajal in thecontrol of gut motility. Br J Surg 1997;84(4):445–50.

[13] Bauer S, Corless CL, Heinrich MC, et al. Response to imatinib mesylate of agastrointestinal stromal tumor with very low expression of KIT. CancerChemother Pharmacol 2003;51(3):261–5.

[14] Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in afamily with multiple cases of gastrointestinal stromal tumor. Gastroenterology2004;126(1):318–21.

[15] Carney JA. Gastric stromal sarcoma, pulmonary chondroma and extra-adrenalparaganglioma (carney triad): natural history, adrenocortical component andpossible familial occurrence. Mayo Clin Proc 1999;74(6):543–52.

[16] Roberts PJ, Eisenberg B. Clinical presentation of gastrointestinal stromaltumors and treatment of operable disease. Eur J Cancer 2002;38(Suppl5):S37–8.

[17] Rader AE, Avery A, Wait CL, et al. Fine-needle aspiration biopsy diagnosis ofgastrointestinal stromal tumors using morphology, immunocytochemistryand mutational analysis of c-kit. Cancer 2001;93(4):269–75.

[18] Stroobants S, Goeminne J, Seegers M, et al. 18FDG-positron emissiontomography for the early prediction of response in advanced soft tissuesarcoma treated with imatinib mesylate (glivec). Eur J Cancer2003;39(14):2012–20.

[19] Miettinen M, El Rifai W, Sobin HL, et al. Evaluation of malignancy andprognosis of gastrointestinal stromal tumors: a review. Hum Pathol2002;33(5):478–83.

[20] DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromaltumors: recurrence patterns and prognostic factors for survival. Ann Surg2000;231(1):51–8.

[21] Joensuu H, Fletcher C, Dimitrijevic S, et al. Management of malignantgastrointestinal stromal tumours. Lancet Oncol 2002;3(11):655–64.

[22] Crosby JA, Catton CN, Davis A, et al. Malignant gastrointestinal stromal tumorsof the small intestine: a review of 50 cases from a prospective database. AnnSurg Oncol 2001;8(1):50–9.

[23] Pierie JP, Choudry U, Muzikansky A, et al. The effect of surgery and grade onoutcome of gastrointestinal stromal tumors. Arch Surg 2001;136(4):383–9.

[24] Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinibmesylate in advanced gastrointestinal stromal tumors. N Engl J Med2002;347(7):472–80.