Educational Case: Gastrointestinal stromal tumor (GIST)

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://doi.org/10.1016/j.acpath.2023.100086.¹

Primary objective

Objective GT3.2: Molecular Basis of Gastrointestinal Neoplasms. Summarize the molecular basis and clinicopathologic features, local and systemic, for esophageal cancer, gastric cancer, GI lymphoma, gastrointestinal stromal tumor, colon cancer, and anal cancer.

Competency 2: Organ System Pathology; Topic: Gastrointestinal tract (GT); Learning Goal 3: GI Neoplasia.

Secondary objectives

Objective N1.1: Genetic Mechanisms of Neoplasia. Discuss and provide examples of molecular genetic mechanisms that underlie cancers, including germline mutations, somatic mutations (including point mutations, deletions, amplifications, and translocations), epigenetic changes, and DNA repair gene effects.

Competency 1: Disease Mechanisms and Processes; Topic: Neoplasia (N); Learning Goal 1: Genetic Basis of Neoplasia.

Objective N3.1: Morphologic Features of Neoplasia. Describe the essential morphologic features of neoplasms and indicate how these can be used to diagnose, classify, and predict the biological behavior of cancers.

Competency 1: Disease Mechanisms and Processes; Topic: Neoplasia (N); Learning Goal 3: Characteristics of Neoplasia.

Patient presentation

A 75-year-old woman presents to the emergency department with sudden onset of severe abdominal pain for the past 8 hours. The pain is localized to the lower abdomen, with increasing severity and frequency and is not subsiding with on nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. She does not report any history of trauma. The patient does not report weight loss or chills. However, the patient does report fever, dark red-black diarrhea, and non-bloody vomiting that started a few days prior to the visit to the emergency room. The patient also reports lethargy and fatigue, which started a month ago and have shown worsening progression. The patient's past medical history includes type II diabetes mellitus, hypertension and chronic obstructive pulmonary disease presents. The patient has no personal or familial history of chronic illness or cancer. Her social history includes being a current smoker. The patient has not traveled out of the country recently. The patient takes medications for type II diabetes mellitus and hypertension.

Diagnostic findings, Part 1

The vital signs include a fever of 103.1 °F (range: 97.8°F–99 °F), blood pressure of 165/80 mmHg (range: <120/80 mmHg), heart rate of 100 beats per minute (range: 60–99 beats per minute), respiratory rate of 16 breaths per minute (range: 12–16 breaths per minute), and pulse oximetry of 98% (range: 95–100%). For the physical examination, upon inspection, there are no lesions or masses on the external skin surface. Auscultation reveals normal bowel sounds in the upper quadrants; however, bowel sounds are decreased sounds in the lower abdomen. Palpation reveals severe lower abdominal pain. Percussion of the liver span, spleen tip, kidneys, and aorta reveal no significant abnormalities.

Questions/discussion points, Part 1

What are the potential differential diagnoses based on analysis of the patient's presentation?

The patient's presentation and physical exam reveal severe lower abdominal pain with associated fever, dark red-black tarry stool and non-bloody vomiting. These findings are concerning for a possibly acute abdominal process or an acute-on-chronic abdominal process, but more specifically are concerning for an upper gastrointestinal (GI) bleed.

Upper GI bleeding can present with hematemesis, which is vomiting of fresh blood, coffee-ground emesis and/or melena (black tarry stool).² Upper GI bleeding is defined as hemorrhage from the mouth to the ligament of Treitz.³ Causes of upper gastrointestinal bleeding in adults include peptic ulcer disease, esophagitis, gastropathy/duodenopathy, portal hypertension (varices and portal hypertensive gastropathy), vascular lesions, traumatic or iatrogenic (Mallory-Weiss syndrome, Cameron lesions, and aortoenteric fistulas), and upper gastrointestinal tumors.⁴ On the contrary, hematochezia (red or maroon blood in the stool) is usually due to lower GI bleeding.⁵ The most common causes of lower gastrointestinal bleeding are: diverticulosis, hemorrhoids, ischemic colitis, inflammatory bowel disease, and colon cancer/polyps.⁶ For both upper and lower gastrointestinal bleeding, the diagnostic and therapeutic modalities are similar such as endoscopic/colonoscopy, computed tomography (CT) scan, and angiography.

What studies are most useful for narrowing the differential diagnosis and how?

Both laboratory and imaging studies are needed to determine the location as well as the nature of the disease process. Laboratory studies include complete blood count (CBC, to include differentials and platelets), iron studies, and a comprehensive metabolic panel (CMP).

The most widely used diagnostic imaging tests for GI lesions include CT, endoscopic procedures (upper endoscopy and colonoscopy), CT angiogram (CTA) and catheter angiography. The diagnostic tool of investigation would be guided by the suspected location of the GI bleed.⁷ All of these modalities have different diagnostic value. Upper endoscopy specifically an esophagogastroduodenoscopy (EGD) can help detect numerous intraluminal lesions which include esophageal adenocarcinoma, esophageal squamous cell carcinoma and gastric adenocarcinoma. Similarly, colonoscopy can also show intraluminal lesions such as colonic adenocarcinoma.⁸ A CT scan can show the location of the tumor and its size as well as the blood vessels feeding the tumor. It can also help indicate presence of metastatic disease. CTA highlights the blood vessels and is usually less invasive than catheter angiography. In most circumstances, the initial evaluation for suspected GI bleeding would be a CT scan and an endoscopic procedure.

Diagnostic findings, Part 2

Table 1 and Table 2 demonstrate the results from laboratory studies, which include a CBC with differential, CMP, and iron studies. The CMP is within normal limits.

Table 1.

Pertinent results from the patient's laboratory studies.

Component	Patient's value	Range
Complete blood count (CBC)
White blood count (WBC)	8.6 million cells/mcL	3.8–10.6 million cells/mcL
Red blood cell (RBC) count	3.75 million cells/mcL (↓)	4.2–5.4 million cells/mcL
Hemoglobin (Hgb)	9.0 g/dL (↓)	11.6–14.6 g/dL
Hematocrit	27.0 %	34.1–43.3
Mean corpuscular volume (MCV)	70 fL (↓)	80-96 fL
Mean corpuscular hemoglobin (MCH)	30 pg	27.5–33.5 pg
MCH concentration (MCHC)	32.9 g/dL	32.0–36.0 g/dL
Red cell distribution width (RDW)	17% (↑)	11.0–15.0 %
Platelets	180 × 103/μl	156-369 × 103/μl

Table 2.

Patient's iron studies.

Iron (Fe)	7 (↓)	28-170 μg/dL
Total iron binding capacity (TIBC)	550 (↑)	250-420 μg/dL
Iron (Fe) saturation %	10 (↓)	25–50%
Serum ferritin	5 ng/mL (↓)	30–400 ng/mL

Contrasted-enhanced CT scan of the abdomen showed a well-defined soft-tissue mass with heterogenous enhancement, measuring 6.0 x 4.5 × 3.0 cm in the small bowel (duodenum) (Fig. 1).⁹ Upper endoscopy showed a large nonperforating mass in the duodenum. Similarly, endoscopic ultrasound showed a heterogenous hypoechoic lesion measuring 6.0 × 4.5 cm in the duodenum.

Fig. 1.

Contrast enhanced CT scan showing a large, well-defined heterogenous mass in the small intestine (see arrow). CT: computed tomography.

Questions/discussion points, Part 2

Interpret the patient's laboratory findings

The patient's laboratory values indicate severe iron-deficiency anemia, which is consistent with the clinical history of gastrointestinal bleed (Table 1, Table 2).

Interpret the patient's imaging findings

The patient's contrast-enhanced CT and endoscopic as well as endoscopic ultrasound findings demonstrate a nonperforating mass in the upper GI system. The lesion can be non-neoplastic, a benign neoplasm, or a malignant tumor.

Interpret the laboratory and imaging data and describe how these findings support the diagnosis while excluding other causes of microcytic anemia

The patient has low hemoglobin (Hgb), mean corpuscular volume (MCV) and iron, which confirms microcytic anemia, most likely an iron-deficiency anemia. Anemia can be classified into three large groups: microcytic (MCV is < 80 fL), normocytic (MCV is 80–100 fL), and macrocytic (MCV is > 100 fL). Microcytic anemia differentials include anemia of inflammation, thalassemias, and iron-deficiency anemia. Anemia of inflammation shows low serum iron, low total iron binding capacity (TIBC), and normal or high ferritin. Depending on the type of thalassemia, iron studies are usually normal. Anemias may be classified as normocytic or macrocytic and as hemolytic or nonhemolytic, encompassing a broad differential diagnosis; however, none of these entities are relevant in this case, and a comprehensive discussion is beyond the scope of this review.

Based on the patient's presentation, imaging, and laboratory findings, how does this narrow the differential diagnosis?

The imaging results confirmed a mass in the duodenum. Based on the patient's imaging finding of a duodenal mass, the main differential diagnoses would be a reactive non-neoplastic pseudotumor versus a benign or neoplastic process. Duodenal lesions are usually categorized as subepithelial or mucosal. Subepithelial lesions that develop in the duodenum include Brunner's gland tumors, lipomas, gastrointestinal stromal tumors, and well-differentiated neuroendocrine tumor (carcinoid). In contrast, mucosally based duodenal lesions include solitary Peutz–Jeghers polyps, and both nonampullary and ampullary adenomas. In this specific case, the patient's mass involved the duodenal mucosa causing bleeding.

What is the next step for reaching a definitive diagnosis?

Given the patient's clinical presentation, laboratory studies, imaging findings and associated differential diagnosis, a tissue biopsy or surgical resection of the mass would provide a definitive diagnosis. The histologic sections from the biopsy or surgical resection specimen will demonstrate the tissue architecture of the lesion and help further classify it. Histologic tissue samples can also be used for ancillary studies, such as immunohistochemistry, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) molecular testing for further subclassification.

Diagnostic findings, Part 3

A resection of the tumor is performed.

Questions/discussion points, Part 3

What histologic features does the tumor show?

Histologic sections (Fig. 2A and B) demonstrate a tumor comprised of uniform spindle cells arranged in sheets and fascicles. The nuclei are monomorphic, with fine chromatic and inconspicuous nucleoli. The cytoplasm is pale and eosinophilic.

Fig. 2.

Histomorphologic features of gastrointestinal stromal tumor (GIST). (A). Uniform spindle-cell proliferation arranged in sheets and fascicles (H&E, 10x). (B). The tumor cells are monomorphic in nature, with fine chromatin and eosinophilic cytoplasm (H&E, 20x).

Based on the histologic findings, what are the differential diagnoses?

Based on this morphology, the differential diagnosis includes spindled gastrointestinal mesenchymal neoplasms including gastrointestinal stromal tumor (GIST), schwannoma, leiomyoma, and leiomyosarcoma.

What special stains or immunostains could be used to narrow the differential diagnosis further?

Gastrointestinal stromal tumors are the most common nonepithelial mesenchymal tumors of the gastrointestinal system which arise from or differentiate toward interstitial cells of Cajal (ICC). CD117 or C-kit is often diffusely positive in these tumors, with cytoplasmic or membranous expression. DOG1 is also diffusely positive, with cytoplasmic or membranous expression. Both CD117 and DOG1 have similar sensitivities and specificities however, in 50% of CD117-negative GISTs, DOG1 will be positive, thus proving to be a useful 2nd line diagnostic marker.10, 11, 12 Both smooth muscle actin (SMA) and desmin are myoid markers that are helpful in excluding a leiomyoma or leiomyosarcoma. Nerve sheath markers, in particular S100 and Sox10, can be used to rule out a gastrointestinal schwannoma. TLE1 and keratins are helpful in ruling out a synovial sarcoma, and both myoid markers, SMA and caldesmon, will exclude a gastrointestinal glomus tumor. Melanocytic markers, including HMB45 and MelanA, would exclude a PEComa. Lastly, Keratins and CD56 can be used to rule out gastroblastoma.

What molecular testing can help in providing a more specific interpretation?

In this setting next generation sequencing (NGS) will be most helpful in further diagnosing, characterizing the tumor, and guiding therapy. NGS is a molecular technology whereby several DNA or RNA sequences are targeted and analyzed to identify genetic variations associated with neoplastic processes for diagnostic or targeted therapy purposes.

Diagnostic findings, Part 4

In this case, immunohistochemical staining demonstrated that the tumor is diffusely positive for CD117 and DOG1 (Fig. 3A and B). All other markers, including S100 (Fig. 3C), desmin (Fig. 3D) SMA, STAT6, and Sox10, were negative. Molecular genetic studies showed mutations in KIT at exon 11.

Fig. 3.

(A). CD117 immunostain is diffusely positive in tumor cells (10x), (B). DOG1 immunostain is diffusely positive in tumor cells (10x), (C). S100 immunostain is negative in tumor cells (20x) and (D). Desmin immunostain is negative in tumor cells (20x).

Questions/discussion points, Part 4

Given the patient's immunostains and molecular findings, what is the patient's final diagnosis?

Based on the tumor's morphologic features (Fig. 2A and B), immunohistochemical studies (Fig. 3A and B), and molecular studies, the overall findings are most compatible with a GIST. Gastrointestinal smooth muscle neoplasms, leiomyoma and leiomyosarcoma, will have negative CD117 and DOG1 expression. Leiomyomas are commonly found in the esophagus and will stain positive for SMA and Desmin. Leiomyosarcoma will show nuclear pleomorphism with SMA and desmin positivity and will usually carry multiple molecular alterations with p53 mutation being the most common. Both of these smooth muscle neoplasms lack KIT and PDGFRA mutations that are characteristic of GIST.^13,14 Gastrointestinal Schwannoma will have a fascicular and occasionally palisaded architecture with negative CD117 and DOG1 expression and positive staining for S100 and Sox10. These tumors will also lack KIT and PDGFRA mutations seen in GIST, and NF2 mutations commonly seen in soft-tissue schwannomas.¹⁵ Other broadened differential diagnoses include solitary fibrous tumor, synovial sarcoma, gastroblastomas and PEComas. Solitary fibrous tumor will show “staghorn” vasculature with STAT6 positive expression and negative CD117 and DOG1 stains. Additionally, solitary fibrous tumors usually harbor NAB2::STAT6 fusion.¹⁶ Synovial sarcoma will often be hypercellular with dense fascicles and will be positive for keratins, TLE1 and SS18-SSX immunostains. Synovial sarcomas are usually negative for CD117 and DOG1 and will characteristically have SS18 rearrangements.¹⁷ Gastrointestinal glomus tumor will often arise from the stomach. This entity is comprised of bland epithelioid cells arranged in nests and can closely resemble epithelioid GIST. Such tumors are diffusely positive for SMA and caldesmon, are negative for CD117 and DOG1, and are commonly associated with NOTCH gene rearrangements.¹⁸ Gastroblastomas usually harbor MALAT1::GLI1 fusion. PEComas are usually positive for SMA and melanocytic markers, HMB45 and MelanA. At the molecular level, PEComas frequently harbor alterations of TSC1 or TSC2 genes and in a minority of cases TFE3 gene rearrangements.¹⁹ Table 319, 20, 21, 22, 23, 24, 25, 26 shows an expanded list of mesenchymal tumors of the gastrointestinal tract with key histologic features, immunohistochemical profiles and molecular characteristics.

Table 3.

Expanded mesenchymal tumors of the gastrointestinal tract with key histologic features, immunohistochemical profiles, and molecular characteristics.

Entity	Histologic features	Immunohistochemical profile	Molecular features	Miscellaneous findings
Gastrointestinal stromal tract tumor (GIST)21	•Spindled, epithelioid or mix type	•CD117 and DOG1 (+) •Loss of SDHB in SDH-deficient GIST	KIT or PDGFRA mutations	•Mesenchymal neoplasm arising from or differentiating from interstitial cells of Cajal (ICC)
Gastroblastoma22	•Multinodular proliferation centered within muscular propia •Epithelial cells and spindle cells	•Epithelial cells are pancytokeratin (+) •Spindle cells CD56 and CD10 (+) •CD117 and DOG1 (−)	MALAT1::GLI1 fusion	•Biphasic gastric neoplasm occurring in young adults
Gastrointestinal schwannoma23	•Interlacing spindled cells	•S100, SOX10 and GFAP (+) •SMA, desmin, CD117 and DOG1 (−)	Lack alteration of NF2	•Peripheral nerve sheath tumor with Schwannian differentiation
Gastrointestinal smooth muscle neoplasms (leiomyoma- LM or leiomyosarcoma- LMS)24	•Benign LM- cytologic features of smooth muscle, no pleomorphism •Malignant LMS- marked pleomorphism and mitosis/necrosis	•SMA, h-caldesmon and desmin (+) in LM •Desmin and caldesmon (−) or focal in LMS •CD117, DOG1, SOX10 and S100 (−)	Multiple molecular alteration; TP53 mutation is most common	•Mesenchymal tumors in GI tract with smooth muscle cells
Solitary fibrous tumor25	•“Staghorn” vascular pattern •Fibrous stroma with collagen	•CD34 and nuclear STAT6 (+) •Keratin, S100, desmin, CD117 and CD31 (−)	NAB2::STAT6 fusion	•Fibroblastic mesenchymal neoplasm with branching vascular pattern
Synovial sarcoma26	•Biphasic tumors with epithelioid structures	•Keratin and EMA (+) •Strong diffuse TLE-1 (+) and/or SS18-SSX (+)	T(X; 18)(p11; q11) with SS18::SSX1/SSX2/SSX4 fusion	•Found in deep soft tissue extremities
Gastrointestinal glomus tumor20	•Perivascular neoplasm with modified smooth muscle cells of normal glomus body •Hyalinized to myxoid stroma	•SMA and caldesmon (+) •Desmin, S100, SOX10 and keratin (−)	NOTCH rearrangements	•Seen in young adults (20–40 years)
PEComa19	•Spindle cell nests with thin-walled capillary vessels in between	Myomelanocytic immunophenotype- SMA, desmin and caldesmon (+) and HMB-45, Melanin-A and MITF (+)	•Frequent alterations of TSC1 or TSC2 gene with activation of mTOR pathway •SFPQ::TFE3 fusion most common	•Mesenchymal neoplasm arising from perivascular epithelioid cells

What are the distinctive features of gastrointestinal stromal tumor?

Gastrointestinal stromal tumor is a mesenchymal neoplasm with variable behavior characterized by differentiation from interstitial cells of Cajal which serve as gastrointestinal pacemakers. GIST can occur anywhere along the GI tract in the following order: stomach > small intestine > colon and rectum > esophagus, whereby it grows from the submucosal layers, specifically the muscularis propria, and it can involve the lumen or serosal surfaces.²⁷ Population based studies indicate an incidence of 1.1–1.5 cases per 100,000 person-years with a median age of diagnosis at 60 years old.²⁸ Most GISTs are sporadic with 5–10% occurring in association with syndromes.²⁹ Most syndromic GISTs are SDH-deficient including those associated with Carney Triad and autosomal dominant Carney–Stratakis syndrome.³⁰ Additionally, GISTs can vary in size, ranging from incidental to large lesions measuring >20 cm. Larger lesions will show hemorrhage and necrosis.

Histologically, GISTs exhibit a broad morphological spectrum, which is often influenced by location-gastric versus small bowel. Gastric GISTs are tumors with epithelioid morphology which can show nodules and fibrotic components with increased cellularity.³¹ Small intestinal and colonic GISTs are spindle cell tumors with diffuse sheets or vague whorled arrangements of the tumor cells. These tumors will have extracellular collagen globules.³²

What are the molecular/genetic findings in gastrointestinal stromal tumor?

Most gastrointestinal stromal tumors, about 85%, will harbor gain-of-function mutations in KIT or PDGFRA oncogenes. Approximately 60–70% of patients with GIST harbor somatic tumor mutations in KIT.^33,34 There is genomic diversity among exon mutation variations in KIT mutations. Most of the KIT-mutant GISTs will have a KIT exon 11 mutation, while 10–15% will be affecting KIT exon 9 and 1% affecting exons 13, 17, and 18.^34,35 After KIT mutations, PDGFRA mutations are the second most common mutations in GIST, with 10% of GISTs having PDGFRA mutations in exon 18, and these tumors are often located in the stomach. The most common PDGFRA mutations are p.D842V and p.V561D.³⁶ Finally, 7% of GISTs will have germline mutations in SDH genes.^37,38 Table 4 highlights the most common gene mutations in GIST and their clinically relevant associations.

Table 4.

List of most common gene mutations in GIST and their associations.

GIST gene mutations	Gene associations
KIT exon 11 mutation	Most common gastrointestinal stromal tract tumor (GIST) mutation, associated with small intestinal, colorectal or esophageal GIST, spindled tumor morphology with extracellular collagen globules.
KIT exon 9 mutation	Second most common KIT gene mutation, similar associations to KIT exon 11 mutation
KIT exon 13, 17, and 18 mutations	Rare, similar associations to KIT exon 11 mutation
PDGFRA p.V561D mutation	Associated with gastric GIST and epithelioid and nodular tumor morphology
PDGFRA p.D842V mutation	Leads to tumor resistance to imatinib and increased responsiveness to avapritinib
SDH gene complex	Associated with Carney triad and autosomal dominant Carney–Stratakis syndrome

What is the prognosis for a patient with a diagnosis of gastrointestinal stromal tumor?

The overall prognosis for GIST is based on the following parameters: mitotic activity, tumor size, and anatomical site. These prognostic parameters are best applied to KIT/PDGFRA mutant GISTs. Tumors <2 cm are associated with a low risk of metastasis. The tumor site is also an important factor. Small-intestinal, colorectal, and esophageal GISTs are more likely to be clinically aggressive compared to gastric GISTs. Guidelines for risk assessment of primary GIST at different sites are classified by miotic rate, size, and risk of progressive disease per location (gastric, duodenum, jejunum/ileum, and rectum).^39,40 The prognosis system does not predict the behavior of SDH-deficient GISTs. Tumors with low mitotic counts can metastasize, while tumors with higher mitotic counts may remain indolent for periods of time.⁴⁰

What is the management of localized disease?

Currently, surgery remains the main modality of treatment of localized GIST. The surgical procedure is to resect the tumor with histologically negative margins.³⁸ Small GISTs are considered to measure less than 2 cm, while mini-GISTs are 1–2 cm in size.⁴¹ Most small GISTs are found in the stomach and diagnosed incidentally during endoscopy or are obtained from other procedures, such as gastric sleeve resections or other cancer procedures. A small percentage of GISTs are found in the small intestine, colon, and rectum. These tumors will have higher mitotic rates and worse prognoses than small gastric GISTs.²⁰

GIST is often seen in older adults; however, a small percentage can be seen in adolescent and young adults. These patients are more likely to have small intestine GISTs, which are also managed operatively.⁴²

What are indications for adjuvant and neoadjuvant therapy?

While surgical resection often is sufficient for GIST management, adjuvant and neoadjuvant therapy with tyrosine kinase inhibitors may be required. Adjuvant therapy (i.e. imatinib, a tyrosine kinase inhibitor) is used for localized GIST under certain circumstances. The modified National Institute of Health (NIH) criteria for high-risk GIST patients and those with likely recurrences includes tumor size, mitotic rate, tumor location and tumor rupture. High risk of recurrence is based on the following criteria: tumor size greater than 10 cm, mitotic activity greater than 10 per 5mm², and the presence of tumor rupture, or tumor size greater than 5 cm with a mitotic index of 5 per 5 mm². Patients with a high risk of recurrence may benefit from adjuvant therapy.⁴³

Neoadjuvant therapy is often used for locally advanced GIST especially in cases of difficult anatomic locations (rectum, esophagus, esophagogastric junction, and duodenum) or in situations where surgical intervention would further expedite morbidity. Neoadjuvant therapy is based on the mutational profile of the tumor. For example, a GIST with a PDGFRA D842V mutation is resistant to imatinib but responsive to avapritinib.^38,44,45

What is the management for metastatic and unresectable GISTs?

For metastatic and unresectable GISTs the main treatment involves systemic therapy. Table 546, 47, 48, 49, 50, 51 demonstrates the currently approved Food and Drug administration systemic therapy with indications for use.

Table 5.

FDA approved systemic therapies.

Drug name	Mechanism of action	Indication
Imatinib46	Selective tyrosine kinase inhibitor	First line therapy however most patients develop resistance to the drug
Sunitinib47	Tyrosine kinase inhibitor	Second line therapy with both antitumor and antiangiogenic activity targeting multiple receptors: VEGFR1, VEGFR2, PDGFRA, PDGFRB, KIT, FLT3, RET and CSF1R
Regorafenib48	Tyrosine kinase inhibitor	Multiple targets such as: angiogenic (VEGFR1-3, TIE2), stromal (PDGFRB, FRGFR), and oncogenic (KIT, RET, and RAF).
Ripretinib49	Tyrosine kinase inhibitor	Selective for KIT mutant GISTs
Avapritinib50	Tyrosine kinase inhibitor	PDGFRA mutant GIST
Larotrectinib and Entrectinib51	Tyrosine kinase inhibitor	Inhibitors of TRK family of proteins

FDA: Food and Drug Administration; GISTs: gastrointestinal stromal tract tumor.

Teaching points

• •GISTs harbor KIT mutations, at a frequency of 70%, mostly in exon 11 and PDGFRA mutations, at a frequency of 10%, mostly in exon 18.³³
• •Gastrointestinal stromal tumors are the most common nonepithelial mesenchymal tumors of the gastrointestinal system and originate from progenitor cells which differentiate toward the interstitial Cajal cells.^35,52 The most frequent disease symptom is hematemesis or melena. Other symptoms can include chronic abdominal pain and chronic anemia.³⁵
• •In the gastrointestinal tract, GISTs grow from the submucosal layers and can involve the lumen or serosal surfaces.⁵³
• •Histologically, GISTs can be either spindle cell or epithelioid. These cells can be arranged in a myriad of patterns, including diffuse, storiform, fascicular, or organoid.⁵⁴
• •Immunohistochemical evaluation demonstrates the tumor to be positive for CD117 (c-KIT) and DOG1. Additionally the tumor will also stain positive for PDGFRA and SDHB in SDH-deficient GISTs.¹⁰
• •In the differential diagnosis for GISTs, both schwannomas and leiomyomas need to be ruled out. Schwannomas are benign peripheral nerve sheath tumors composed of Schwann cells and are defined by strong and diffuse S100 positivity while leiomyomas are smooth muscle neoplasms which are mostly smooth muscle actin (SMA)- and desmin-positive but negative for S100.
• •Other tumors in the differential diagnosis include solitary fibrous tumor which carries a NAB2:STAT6 fusion. Synovial sarcoma is defined by SS18 rearrangements. Gastrointestinal glomus tumor is associated with NOTCH rearrangements. Gastroblastoma characteristically harbors a MALAT1:GLI1 fusion. Lastly PEComa has frequent TSC1/TSC2 alterations and occasional TFE3 rearrangements.
• •Clinical diagnostic tools include both endoscopic examination and imaging techniques. Surgical resection is often the first line treatment in adjunct with adjuvant or neoadjuvant therapies with tyrosine kinase inhibitors.³²

Funding

The article processing fee for this article was funded by an Open Access Award given by the Society of ‘67, which supports the mission of the Association for Academic Pathology to produce the next generation of outstanding investigators and educational scholars in the field of pathology. This award helps to promote the publication of high-quality original scholarship in Academic Pathology by authors at an early stage of academic development.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.