INTRODUCTION
Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal tumor of the gastrointestinal (GI) tract.[12] GIST can arise in any portion of the GI tract; however, the stomach (40%–60%) is the most common site followed by the small intestine (30%–40%).[3]
GISTs originate or differentiate toward cells showing morphological and immunophenotypic similarities with the interstitial cells of Cajal (ICC). Several subpopulations of ICC have been described and these include submucosal, septal, deep muscle plexus, intramuscular, myenteric, and subserosal ICC.[4] GISTs usually arise from the muscular layers of the GI tracts (muscularis mucosa or propria). GIST arising from the serosa is rare, with handful of cases reported in the last few years.[5678]
CASE HISTORY
We report the case of a 46-year-old woman who presented to the gynecology clinic on account of progressive abdominal mass of 3 years and abdominal pain of 6-month duration. Physical examination revealed a tender left abdomino-pelvic mass measuring approximately 20 cm × 18 cm × 18 cm, extending from the left pelvic area to the supra-umbilical region. Clinical impression was suspected ovarian mass. The ultrasonography showed a thick-walled heterogeneous mass arising from the left pelvic region and extending to the supra-umbilical region. The bowels were reported to have normal wall thickness and intraluminal diameter with normal peristalsis observed. The computed tomography (CT) scan however showed a huge, well-circumscribed mass appearing to arise from the mesentery in the left lower abdominal area with solid and cystic components and no evidence of any connection with the left adnexal structures. The bowels showed normal caliber and wall thickness. No nodal involvement or features suggestive of metastatic deposits were seen. An impression of mesenteric desmoid tumor was made.
The patient underwent an exploratory laparotomy and intraoperative findings included a huge cystic mass arising from the anti-mesenteric border of the small intestine (ileum) approximately 228 cm from the duodenojejunal junction, displacing the bowel to the right upper quadrant. The mass was not invading nearby organs or structures. The left adnexal structures were unremarkable. The mass contained approximately 5 L of hemorrhagic effluent seen in the theatre. The ileum was resected along with the mesenteric mass and sent for histological diagnosis.
Gross examination showed a segment of small intestine measuring 10 cm in length with an attached huge fleshy to tan cystic mass measuring 14 cm × 16 cm × 16 cm at the anti-mesenteric area. The mass was cut open to reveal fleshy to cystic surface with a core of degenerated hemorrhagic tissue with a diameter of 12 cm [Figure 1].
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Figure 1: Gross photograph of the cut section of the serosal mass consisting of partly solid gray to tan areas with hemorrhagic and necrotic core
The intestinal segment showed patent lumen with preserved mucosal folds with no mass lesion seen.
The histological sections showed small intestinal tissue with the tumor located at the serosal layer and separate from the intact muscular layer [Figure 2]. The tumor cells are disposed in short whorls, fascicles, nodules, and in diffuse sheets. They show pleomorphic, hyperchromatic plump to spindle nuclei with prominent nucleoli and areas of brisk mitotic activity (5 per 10 high-power fields) with atypical mitoses [Figure 3]. There are also extensive areas of necrosis. The stroma is scant and composed of loose fibromyxoid areas with interspersed thin-walled vascular channels. The resected margins were free of the tumor.
Figure 2: Histological sections at low power showing the proliferating mesenchymal cells in the serosal layer seen separate from the preserved muscularis propria (black arrow). H/E ×40
Figure 3: Histological sections at medium power showing short whorls of spindle-shaped cells with fairly pleomorphic, hyperchromatic nuclei, and scant faintly eosinophilic to clear cytoplasm. Some thin-walled vascular channels are seen. An atypical mitotic figure is seen at the top left corner (blue arrow). H/E ×100
Based on the morphological features, a preliminary diagnosis of GIST was made. However, other differentials considered include neural sheath tumor, inflammatory myofibroblastic tumor and de-differentiated liposarcoma.
Immunohistochemical (IHC) studies done showed CD117++, DOG1++, Ki67 20%–25%, CD34–, SMA–, desmin–, ALK–, panCK– and S100–[Figures 4-6].
Figure 4: Microscopic section showing the spindle tumor cells with membrane and cytoplasmic positivity with c-KIT/CD117. IHC ×400
Figure 5: Microscopic section showing the spindle tumor cells with membrane and cytoplasmic positivity with DOG1. IHC ×100
Figure 6: Microscopic section showing approximately 25% of tumor cells showing nuclear expression of Ki67. IHC ×400
DISCUSSION
GIST is the most common mesenchymal tumor of the GI tract and accounts for 1%–3% of GI neoplasms.[129] They are believed to arise or differentiate toward ICC, an important part of the GI autonomic nervous system functioning as a pacemaker system within the walls of the GI tract.[1] GISTs usually originate in the stomach or small intestine but can occur anywhere along the GI tract such as the colon, rectum, appendix, esophagus. Involvement of sites outside the GI tract such as the omentum and retroperitoneum are very rare.[71011] GISTs in the omentum, mesenteries, and retroperitoneum are usually metastasis from a GI origin or possibly detached from their GI origin. Only very few have been reported as primaries from these sites.[56812]
Expression of the c-KIT proto-oncogene is essential for the development of GIST.[11] Hence, they are tumors with mutations in the KIT gene or platelet-derived growth factor receptor alpha (PDGFRA) gene,[13] and thus immunohistochemical recognition of KIT protein expression (CD117) is a reliable diagnostic marker of the disease. The c-KIT proto-oncogene located on chromosome 4q 11–12 encodes the transmembrane tyrosine kinase KIT.[14] Gain-of-function mutation of c-KIT was first discovered and reported in human GISTs in 1998.[15]
These activating mutations lead to hyperplasia of the ICCs and GISTs. Mutation of KIT with constitutive activation of tyrosine kinase is found in the majority (75%) of GISTs, whereas PDGFRA gene mutation occurs in approximately 10% of cases.[16] Approximately 15% of GISTs do not have detectable KIT or PDGFRA gene mutation, but have germ-line mutation in the SDH gene and are termed “wild-type” GISTs. Other genetic mutations detected in wild-type GISTs include BRAF, HRAS, NRAS, and PIK3CA. Certain syndromes have been reported to be associated with GIST such as neurofibromatosis type 1, Carney-Stratakis syndrome, and Carney triad.[16]
GISTs of the small intestine are often asymptomatic because most of them grow in an exophytic pattern till they are large in size.[57] The median size of GISTs in the small intestine has been reported to be as large as 7 cm at the time of diagnosis,[17] whereas those greater than 10 cm in diameter have been termed as giant GISTs.[18] Patients present with highly variable, non-specific clinical symptoms such as GI bleeding, vague abdominal mass, palpable mass and even fever.[17] The standard investigation of choice for evaluation of tumor size, location, and metastases is contrast-enhanced CT imaging.[7]
In this index case, the tumor was much larger than those earlier reported; it measured approximately 16 cm in its widest diameter and yet no GI symptoms were reported by the patient. This is understandable considering the unusual location as the mass did not compromise the luminal integrity of the small intestine. The radioimaging investigations did not reveal the intestinal origin of this mass and this was only realized intraoperatively.
Complete surgical resection is the only potential curative treatment for GISTs.[71920] For small intestinal GISTs, resection of segments of the intestine with the tumor is the standard surgical management. However, the tumor should be handled with great care because rupture of the pseudocapsule may lead to tumor dissemination and poor prognosis.[1921]
GISTs are well-defined, unencapsulated tumors that are firm in consistency and gray-white in color. Smaller masses have a homogeneous cut surface, whereas large lesions may show areas of necrosis and hemorrhage with cystic degeneration. Microscopically, GISTs show three histological patterns: the spindle cell type which is the most common type (70%), epithelioid type (20%–25%), and mixed spindle cell and epithelioid type. They usually vary from hypocellular to highly cellular tumor with higher mitotic activity.[22] The vast majority of GISTs (95%) are strongly and diffusely positive for c-KIT (CD117), hence making it a specific and sensitive marker in differentiating GIST from other histologically similar mesenchymal tumors in the GI tract.[223] DOG1 has similar sensitivity and specificity as CD117 and in fact is expressed in most tumors that do not express CD117, making it a valuable second-line diagnostic marker for GIST. A minor subset of GISTs especially of small intestinal origin reacts positively with h-caldesmon and Smooth Muscle Actin (SMA). Generally, these tumors do not show reactivity with S100, desmin, and cytokeratins, but rare exceptions have been reported showing focal reactivity.[2] Less than 5% of GISTs show negative reactivity to CD117. These tumors have mutations that activate PDGFRA and may also be inhibited by imatinib.[23] Imatinib mesylate, a tyrosine kinase inhibitor that targets KIT, has been shown to improve prognosis after radical resection of high-risk GISTs.[724] Approximately 70% of GISTs express CD34 on IHC.[6]
The main differential diagnosis of GIST includes smooth muscle tumors, schwannoma (intensely positive for S100-protein, but negative for CD117), desmoid fibromatosis (CD117-negative), inflammatory myofibroblastic tumor (both negative for CD117 and CD34), inflammatory fibroid polyp, solitary fibrous tumor (CD117-negative), synovial sarcoma, and melanoma (HMB45 and Melan A-positive).[25] The accurate diagnosis of GIST is critical as the treatment differs from other differentials. This is even more important in low-resource practice settings, where access to ancillary testing is very difficult.
Metastases have been reported in approximately 50% of cases in GISTs, with the liver (65%) being the most frequent organ, followed by the peritoneum (21%). Other sites of metastasis include the retro-peritoneum and the brain. Metastases to lymph nodes, lungs, and bones are rare.[621]
The investigation of choice for staging and follow-up of GIST is contrast-enhanced abdominal and pelvic CT scan, whereas early detection of tumor response to molecular-targeted therapy (such as imatinib) or neoadjuvant therapy is evaluated with fluorodeoxyglucose (FDG) uptake using an FDG-positron emission tomography (PET) scan.[67]
CONCLUSION
GIST is the most common primary mesenchymal neoplasm of the GI tract. It is mostly found in the stomach, whereas a third of cases are seen in the small intestine. However, occurrence in the large intestine and extra intestinal sites is extremely rare. It is important to keep GIST in the differentials when investigating serosal-based tumors of the GI tract even when the radioimaging findings are not consistent. This tumor has broadly variable morphological characteristics, and so it is crucial that it is distinguished from other much uncommon mesenchymal neoplasms through ancillary tests, particularly immunohistochemistry to establish the definitive diagnosis and enable the appropriate management.
Financial support and sponsorship
Not applicable.
Conflicts of interest
There are no conflicts of interest.
Acknowledgement
We would like to acknowledge Prof. Pepe Jiménez Heffernan of Universidad Autónoma de Madrid for providing technical support in the course of the workup for this case.
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