Gastrointestinal stromal tumors (GIST) comprise only 1% of cancers of the gastrointestinal (GI) tract; however are the most common mesenchymal tumors this organ system 1. GISTs are found in all ages but predominate in adults with an average age of incidence between 60 and 70 2. The location of tumor occurrence, in order of frequency, includes the stomach (60-70%), small bowel (20-25%), colon and rectum (5%)1. Although a majority are benign, up to 20-30% are malignant, most commonly in the small intestine3. The etiology is unclear and doesn’t seem related to pre-existing or underlying chronic inflammatory disease of the stomach or bowel4.
Because of their submucosal location, sampling by endoscopy can be attempted but the standard mucosal biopsies are usually insufficient and sampling may be best performed by image-guided FNA or biopsy2. Classification of these tumors is either spindled (70%), or less commonly, epithelioid (20%)2. In the spindled type, tumor aspirates are composed of irregular groups or fascicles of spindle-shaped cells with wispy cytoplasmic extensions. Perinuclear/paranuclear vacuoles may be seen5. In the epithelioid variant there are round cells with round nuclei which may be arranged in small clusters and singly with ample cytoplasm. Malignancy is best determined on histology, however cytologic high mitotic count and necrosis can be suggestive of malignancy. Risk stratification for recurrence is possible dependent on location and tumor parameters like size and mitotic rate. For example, tumors less than or equal to two centimeters, regardless of location, and less than or equal to five mitoses per HPF, confer no risk of poor outcome. Tumors between 5-10 cm but with less than or equal to five mitotic figures per fifty high power fields (HPF) are considered low risk if located in the stomach. If located in the duodenum or rectum, the same tumor is considered high risk for recurrence/poor outcome. Of note, all tumors located in the jejunum/ileum and rectum, regardless of size and with greater than five mitoses per fifty HPFs, are considered high risk for recurrence6. Metastases are usually to the liver and peritoneum; but bone, retroperitoneum, and soft tissue can also be involved2.
The differential diagnosis of a spindled or classic GIST includes other mesenchymal tumors such as leiomyoma, leiomyosarcoma, schwannoma, fibromatosis, solitary fibrous tumor, but also malignant melanoma. High-grade GISTs may mimic spindle cell carcinoma or malignant fibrous histiocytoma. Less likely, epithelioid GIST may mimic granular cell tumor or even glomus tumor, although malignant melanoma may also be considered.
As these mesenchymal tumors are believed to originate from pacemaker cells of the GI tract, the interstitial cells of Cajal, they are similarly immunoreactive for CD117 (c-kit). Most harbor the c-kit mutation, while a minority of GISTs (most c-kit negative) carry the platelet derived growth factor receptor alpha (PDGFRA) mutation. A fairly new key immunohistochemical marker, DOG1 has been found to have superior sensitivity and specificity in these tumors. DOG1 also stains for the interstitial cells of Cajal. Incidentally, this marker can detect up to a third of c-kit negative GISTs7. Although not specific for but in support of GIST, CD34 is also usually positive (60-70%), helping to differentiate from smooth muscle tumors like leiomyoma or leiomyosarcoma8.
Additional immunohistochemical stains may help eliminated differential diagnostic considerations for spindled GIST. For example, smooth muscle tumors would be positive for desmin, smooth muscle actin (SMA); while negative for CD117 and CD34. Tumors of neural origin like schwannoma would stain positive with S100 and be variable, but usually negative, for CD117 and CD34. Fibromatosis may give false positive CD117 staining. Solitary fibrous tumor would stain for CD34 but is negative for CD117. Spindle cell carcinomas would stain positive for keratins and negative for CD117. Malignant fibrous histiocytoma may be focally positive for SMA and vimentin, as well as CD68. Differential diagnostic considerations for epithelioid GIST include granular cell tumor which would be positive for S100, inhibin, and CD68. Glomus tumor would be SMA, calponin, caldesmon positive, but desmin negative. Malignant melanoma should stain positive for S100 and would be DOG1 negative. Of note, S100, desmin , and SMA have been reported positive on occasion in GISTs9.
The two mutations found in GISTs are detected best by molecular tests like polymerase chain reaction (PCR) and sequencing of exons 9, 11, 13, and 17 (for c-kit mutation) and exons 12, 14, and 18 (for PDGFRA mutation) as conventional cytogenetics is not specific enough to detect the genes involved. Most commonly c-kit is mutated on exon 11. It has been reported that rarely, exon 8 may harbor the c-kit mutation, so more sequencing may be necessary in rare cases, as it has prognostic consequences10.
Treatment for GISTs generally includes surgery, if the mass is >2cm. Watchful surveillance may be considered for smaller tumors. At the beginning of this century, tyrosine-kinase inhibitors (TKI) were FDA-approved for unresectable or metastatic GISTs with marked improvement in survival as only 48-70% of resected GISTs had a 5-year disease free survival prior to medical therapy11. Later, Imatinib (Gleevec®) was FDA-approved as adjuvant therapy for c-kit positive GISTs2. For GISTs that progress, or when patients develop resistance to Imatinib, a newer TKI Sunitinib (Sutent®) can be offered2. Sunitinib’s advantage is that it inhibits vascular endothelial growth factor receptor (VEGFR) in addition to targeting c-kit and PDGFRA. In 2013 a new TKI, Regorafenib (Stivarga ®), was approved when therapy with the aforementioned TKIs fails 12. In additional to covering for mutations in c-kit, PDGFRA, and VEGFR, Regorafenib targets mutations in RET, FGFR, and BRAF.