GI stromal tumors (GISTs) are neoplasms with a varying malignancy potential ranging from virtually indolent tumors to rapidly progressing cancers. GISTs occur throughout the intestinal tract, and most harbor an activating mutation in either KIT or platelet-derived growth factor A ( PDGFRA). Diagnosis is made using immunohistochemistry, but molecular testing with mutation analysis is paramount for selection of appropriate therapy. Most small GISTs are cured with surgery. Tyrosine kinase inhibitor (TKI) therapy has led to substantial improvements in survival, both for patients with localized GIST and those with advanced disease. Adjuvant therapy with imatinib benefits patients with a high risk of recurrence, with studies suggesting most benefit with at least 3 years of therapy. Neoadjuvant imatinib therapy should be considered for patients requiring extensive surgery, aiming at shrinking the tumor to allow organ preservation and less extensive surgery. The following three TKIs have been approved for the management of advanced disease: imatinib, sunitinib, and regorafenib; imatinib is usually the best tolerated of the three and the standard first-line treatment. TKIs benefit the majority of patients with advanced GIST but have no or limited efficacy in patients with the PDGFRA D842V mutation or patients with GIST lacking KIT and PDGFRA mutations. Surgery, the mainstay of primary tumor management, also plays a role in the advanced disease setting for selected patients, as do some other approaches such as palliative radiation therapy. Research continues to identify novel therapies, in particular effective agents to treat TKI-refractory disease.

/pdf/gastrointestinal-stromal-tumors-1jmenumang.pdf

Gastrointestinal Stromal Tumors

Introduction
The gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the intestinal tract, known to be refractory to conventional chemotherapy or radiation. Its pathogenesis is defined by mutations within the KIT and PDGFRA gene, which constitutively activate KIT and PDGFRA oncoproteins, and serve as crucial diagnostic and therapeutic targets.

/pdf/gastrointestinal-stromal-tumors-1ij3kfghhz.pdf

Gastrointestinal stromal tumors

Extra-gastrointestinal stromal tumor (EGIST) is a special type of gastrointestinal stromal tumor, which has similar biological characteristics to its counterpart, and occurs outside the gastrointestinal tract. It was identified first by Miettinen et al. [1], and named by Reith et al. [2]. The incidence of EGIST is extremely low, and so far there is no detailed epidemiological figure. To the best of our knowledge, EGIST has been commonly reported in the mesentery, omentum or retroperitoneum [1–4], and sporadically in the pleura [5], pancreas [6–12], liver [13–17], gallbladder [18], adrenal gland [19], bladder [20–22], prostate [23] and vagina [24, 25]. Most existing studies of EGIST are case reports, lacking enough information to clarify the disease; thus it is very difficult to establish helpful guidelines for clinicians. It is very common that EGIST is misdiagnosed for other tumors. Herein, we report an extra-gastrointestinal stromal tumor of the liver, which was diagnosed by ultrasound-guided fine needle aspiration cytology (US-FNAC), and review the literature, so as to help understand EGIST better.

A 53-year-old Chinese man was admitted to the Affiliated Hospital of Guangdong Medical College in July 2011 with the chief complaint of abdominal discomfort in the right upper quadrant for 1 month. The patient denied abdominal pain, diarrhea, nausea, vomiting, hematemesis, hematochezia, fevers or chills. There was no loss of appetite or weight. He had an ultrasound scan three days previously in a local hospital, revealing a giant mass in the liver. He had had sub-total gastrectomy because of gastric ulcer in 2005.

Physical examination showed a well-developed man with abdominal distention; yellow pigmented lesions, hepatic palm and spider angioma were not seen; palpation indicated a large mass extending subcostally approximately 18 cm, moderately tender and non-pulsatile; percussion tenderness over hepatic region and shifting dullness were negative.

Contrast-enhanced computerized tomography of the upper abdomen was performed. It showed a giant irregular low-density mass almost occupying the full right lobe of the liver; it was encircled by rich blood vessels, and the maximum dimensions were about 17 cm × 20 cm; the pancreas and right kidney were dislocated (Figure 1). Chest X-ray showed no abnormal lesions. Tumor markers AFP, CA19-9 and CEA were all negative. Fecal occult blood test was also negative. Both glutamate alanine aminotransferase and glutamic oxaloacetic transaminase were in the normal range. HBsAg, HBeAb and HBcAb were positive in second liver two half-and-half tests.



Figure 1

Contrast-enhanced computerized tomography. Contrast-enhanced CT shows a large mass about 17 cm × 20 cm almost occupying the full right lobe of the liver, which was encircled by rich blood vessels. The pancreas and right kidney were dislocated ...



Due to the patient's condition, hepatectomy could not be performed, and a US-FNAB from the liver mass was taken. Histologically the tumor consisted of spindle cells with pleomorphic nuclei, commonly vacuoles beside the nuclei and abundant intercellular collagen (Figures 2A–B). Immunohistochemical analysis revealed that the spindle cells were positive for CD117 (Figure 3 B), CD34 (Figure 3 A), discovered on GIST1 (DOG-1) (focal) (Figure 3 D), SMA (Figure 2 C), and vimentin (Figure 2 D), while they were negative for CK (Figure 3 C) and S-100 (figure not shown). All these results indicated that the diagnosis was extra-gastrointestinal stromal tumor. The tumor's mitotic activity could not be evaluated because of the small amount of examined material. KIT gene mutation analysis was not performed due to its non-availability at our institute.



Figure 2

Histological and immunohistochemical findings of hepatic EGIST. A – The tumor is composed of spindle cells (hematoxylin and original magnification 200×).B – The spindle cells show pleomorphic nuclei, commonly vacuoles beside the ...





Figure 3

Immunohistochemical findings of hepatic EGIST. A – CD34 positive in tumor cells (original magnification 400×).B – CD117 positive in tumor cells (original magnification 400×).C – CK negative in tumor cells (original ...



We advised the patient to take imatinib mesylate (Glivec), but he refused because of financial problems, and was discharged 13 days later.

Gastrointestinal stromal tumor (GIST) is a common tumor of the gastrointestinal tract, which mainly occurs in the stomach. When this kind of neoplasm develops outside the gastrointestinal tract, it is defined as EGIST. Metastasis of GIST to the liver is very common, while primary GIST of the liver is extremely rare. To the best of our knowledge, only 5 cases of primary hepatic EGIST have been reported previously in English [13–17] (Table I). There is a distinct male predominance, and their age ranges from 17 to 79 years, average 47.7 years. The majority have a large tumor size, only one under 10 cm. Four of 6 cases have a spindle cell type. Both CD117 and CD34 have only one case that is negative. The mitotic rate and outcome are hard to analyze. Due to the particularity of hepatic EGIST, it should be diagnosed differentially with primary or metastatic poorly differentiated carcinoma, angiomyolipoma, leiomyosarcoma, or malignant melanoma. HMB-45 and PKCθ were recommended in immunohistochemical analysis, so as to exclude the mimics mentioned above [17]. 



Table I

Hepatic EGIST reported in the literature



US-FNAC is the quickest and least painful way to obtain an accurate tissue diagnosis of a lump anywhere in the body. There are three steps in US-FNAC: firstly, the position, size and adjacent structure of the lesion are evaluated by ultrasound; secondly, two or more samples are taken with a 23-gauge or 25-gauge needle; lastly, the obtained samples are stained and examined by a pathologist. It has multiple advantages compared to open biopsy, which is not only inexpensive and minimally invasive but is also performed simply and easily. Furthermore, it allows surgery or neoadjuvant treatment to be performed expeditiously with a confirmed preoperative diagnosis. An accurate diagnosis is made with the combination of clinical examination, radiology and FNAC. Although EGIST is rare, it also could be diagnosed by this technique. Rao et al. [26] reported a case and reviewed three cases of pancreatic EGIST, which were diagnosed by US-FNAC. Luo et al. [15] showed that there was no exception on hepatic EGIST. The present case revealed that the biopsy samples were enough for cytological analysis, although the mitotic rate could not be determined.

In order to understand EGIST more clearly, we have reviewed several quite large studies [1–4, 27–30] (Table II) published recently. When these data are summarized together, some similarities can be seen distinctly. The incidence of EGIST is 5%-7% of cases of GIST [4, 28], with a female predominance (64.9%, 98/151), and the most frequent lesion sites are the mesentery, omentum and retroperitoneum [1–4]. The median age is 58.5 years, which is similar to jejunal and ileal GISTs (59 years) [31]. Due to EGIST being outside of the gastrointestinal tract, there are no common symptoms such as bleeding or obstruction. Furthermore, the abdominopelvic cavity and retroperitoneum have enough room for a neoplasm to grow. Thus most of the cases presented a tremendous mass when first detected, with median size of 13.5 cm. Whether the tumor size is a prognostic factor or not, it should be taken into account. Reith et al. [2] found that there were no significant differences between large (> 10 cm) and small (≤ 10 cm) tumors in outcome. The cell morphological pattern of EGIST is predominantly spindle (71 cases) or epithelioid (54 cases). Three studies [1–3], in which the number of patients was more than 20, were in accord with the figure. Spindle cell EGIST should be diagnosed differentially with smooth muscle tumors, schwannoma, solitary fibrous tumor and sarcomatoid carcinoma, while epithelioid EGIST should be diagnosed differentially with metastatic melanoma, carcinoma, clear cell sarcoma and epithelioid hemangioendothelioma [32]. More than one third (55/135) of cases displayed a mitotic index more than 5 per high-power field (HPF). Yamamoto et al. [3] revealed that a high mitotic rate (≥ 5/50 HPF) had significantly shorter disease-specific survival than a low rate (< 5/50 HPF) (p = 0.015). Almost 100% were positive for CD117 [2–4, 29]. We think that it may be because most of them are retrospective studies. The patients were used to being easily misdiagnosed with other diseases. With this type of issue, CD117 was recommended as a selection criterion. CD117-negative tumors should be taken seriously; it still cannot exclude EGIST. Demetri et al. [32] recommended using DOG-1 as a candidate when CD117 immunostaining and mutation testing for KIT and PDGFRA were all negative. About 57.1% (84/147) of patients were CD34-positive, which was lower than GIST (81%) [33]. Other antibody markers were different in these studies; thus it was hard to analyze. Considering the follow-up data from different studies, it is very difficult to reach a persuasive conclusion. However, there is a trend that EGIST is an aggressive group with worse outcome. 



Table II

Summary of clinicopathological features of seven case series of EGIST



In conclusion, we have presented a case of hepatic EGIST diagnosed by US-FNAC. The incidence of EGIST is low, and it has a younger age of diagnosis and large tumor size. The mitotic index can be a prognostic factor; however, tumor size still needs more proof. Furthermore, EGIST can be misdiagnosed for other diseases, and clinicians should take it seriously.

pdf/extra-gastrointestinal-stromal-tumor-of-the-liver-diagnosed-d864hdrflh.pdf

Extra-gastrointestinal stromal tumor of the liver diagnosed by ultrasound-guided fine needle aspiration cytology: a case report and review of the literature.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Rarely, tumors with the same histological and immunohistochemical features arise in organs having no connection to the tubular gastrointestinal tract designated as extragastrointestinal stromal tumors (EGISTs). In this article, we report the first case of an EGIST presenting as a hormonally inactive adrenal mass. A 68-year-old woman with a 3-month history of right abdominal pain was clinically diagnosed as having a hormonally inactive right adrenal tumor sizing 15 cm in diameter. This mass and the tightly fixed right adrenal gland were resected en bloc. Histologically, the tumor was composed primarily of monomorphic spindle cells. Mitotic figure was 2–3 per 50 high power fields. Immunohistochemical analysis revealed strong positivity for CD117 (c-KIT) and smooth muscle actin (α-SMA), but negativity for beta-catenin, CD34, pan-keratin, S-100, desmin, and H-caldesmon. Genetic analysis showed no mutations in KIT gene exons 9, 11, 13, and 17, and in exon 18 of the platelet-derived growth factor-2 receptor gene (PDGFR). The patient proved to be tumor free at the 18-month follow-up. This case under study demonstrates that EGIST should be included in the differential diagnosis of hormonally inactive adrenal tumors. CD117 (c-KIT) immunohistochemistry should be applied in the pathological workup of soft tissue adrenal tumors. This case is an additional example suggesting that the prognosis of even a very large EGIST is not definitely grave.

Gastrointestinal stromal tumor presenting as a hormonally inactive adrenal mass.

Extra-gastrointestinal stromal tumors (EGISTs) predominantly occur outside of the gastrointestinal tract, and their biological and histological characteristics are similar to those of GISTs. Primary EGIST occurrence in the liver is extremely rare. The present study reports a case of primary EGIST in the caudate lobe of the liver in a 61-year-old Chinese man. Contrast-enhanced computed tomography revealed a 7.3×5.1-cm heterogeneously enhanced neoplasm with solid and cystic components located in the caudate lobe of the liver. The patient underwent caudate lobe (specifically, Spiegel lobe) resection. Immunohistochemical analysis of the resected tumor revealed a strong positivity for cluster of differentiation (CD)117, discovered on GIST-1 and CD34. Thus, based on the histological and immunohistochemical findings, the final diagnosis was primary hepatic EGIST. Follow up was conducted at 3-month intervals for the first year and 6-months thereafter. The patient was asymptomatic without any sign of recurrence during the follow-up period. Lab tests were in normal range, and no mass was found in CT scan.

/pdf/malignant-extra-gastrointestinal-stromal-tumor-of-the-liver-kq7dezynxs.pdf

Malignant extra-gastrointestinal stromal tumor of the liver: A case report

Most mesenchymal tumours of the gastrointestinal tract are now referred to as gastrointestinal stromal tumours (GISTs) These tumours typically express c-kit (CD117) and CD34; 30-50% are (often focally) positive for alpha-smooth muscle actin, and all are negative for desmin and S100 protein Recently, mutations in exon 11 of the c-kit gene have been identified as a molecular genetic marker for the subset of GISTs In this report, we describe a mesenchymal tumour removed from the pelvic cavity of a 34-year-old man The tumour was strongly attached to the external wall of the urinary bladder The neoplasm grossly resembled a leiomyoma, and was histologically composed of sheets of spindle cells with a dense collagenous background The mitotic activity was low (less then 1 per 50 high-power fields) Immunohistochemically, tumour cells were negative for alpha-smooth muscle actin and desmin and positive for CD117 and CD34 This case illustrates that tumours which are phenotypically and genotypically similar to GISTs may present in sites other than the tubular gastrointestinal tract

Extragastrointestinal stromal tumor of the urinary wall bladder: case report and review of the literature.

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Extragastrointestinal stromal tumor of the urinary wall bladder: case report and review of the literature.