Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Diagnosis
2.1. Pathological Diagnosis of GIST
2.2. Molecular Aspects of GIST
2.3. Clinical Diagnosis of GIST
2.4. Tissue Acquisition for Pathological Diagnosis
3. Surgery
3.1. Surgical Therapy of Primary GISTs
3.2. Surgical Therapy of Small GISTs
3.3. Laparoscopic Surgery for GISTs
3.4. Risk Evaluation in GIST
4. Medical Therapy
4.1. Medical Therapy for Metastatic/Recurrent GISTs
4.2. Newly Emerging Therapy: New TKIs and Drugs for the NTRK Fusion
4.3. Developing Therapy
5. Conclusions
Authors Contribution
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AFIP | Armed Forces Institute of Pathology |
CSF1R | macrophage colony-stimulating-factor 1 receptor |
CTLA4 | cytotoxic T-lymphocyte-associated antigen 4 |
DFS | disease-free survival |
EGJ | esophagogastric junction |
EMR | endoscopic mucosal resection |
ESD | endoscopic submucosal dissection |
ESEG | European Society of Gastrointestinal Endoscopy |
ESMO | European Society for Medical Oncology |
EUS | endoscopic ultrasonography |
EUS-FNA | EUS-guided fine needle aspiration |
FDA | Food and Drug Administration |
FLT3 | FMS-like tyrosine kinase 3 |
GI tract | gastrointestinal tract |
GIST | gastrointestinal stromal tumor |
GPR20 | G protein-coupled receptor 20 |
HIF-1α | hypoxia-inducible factor-1α |
HR | hazard ratio |
IGF1R | insulin growth factor-1 receptor |
IHC | immunohistochemistry |
IMT | inflammatory myofibroblastic tumor |
LECS | laparoscopic endoscopic cooperative surgery |
MIAB | mucosal incision-assisted biopsy |
NCCN | National Comprehensive Cancer Network |
NIH | National Institutes of Health |
OS | overall survival |
PD-1 | programmed death-1 |
PD-L1 | programmed death-ligand 1 |
PEComa | perivascular epithelioid cell tumor |
PFS | progression-free survival |
RFS | recurrence-free survival |
ROSE | rapid on-site evaluation |
RR | response rate |
RTK | receptor tyrosine kinase |
SDH | succinate dehydrogenase |
SFT | solitary fibrous tumor |
SMT | submucosal tumor |
TKI | tyrosine kinase inhibitors |
Tx | therapy |
VEGFR | vascular endothelial growth factor receptor |
SSTR2 | somatostatin receptor 2 |
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Alterations | Estimated Frequency | Main Location | Characteristics | Sensitivity to Drugs & Potential Drugs | |||
---|---|---|---|---|---|---|---|
KIT mutations in the autoinhibited form | KIT mutation # | exon 9 (or exon 8), typically duplicated insertion of A502-Y503 codons | 5–10% | Small intestine | Spindle cell type Aggressive features | Less imatinib sensitive, sensitive to sunitinib, regorafenib, ripretinib, avapritinib | |
exon 11 (deletions, missense, insertions etc.) | ~60% | All sites | Aggressive features with del 557-558, which is very sensitive to imatinib | Sensitive to imatinib, sunitinib, regorafenib, ripretinib, avapritinib | |||
exon 13 (K642E) | <1% | Sensitive to imatinib, sunitinib, regorafenib, ripretinib, avapritinib | |||||
exon 17 (D820Y, N822K, Y823D) | 1% | Sensitive to imatinib, regorafenib, ripretinib, avapritinib, and less sensitive to sunitinib | |||||
PDGFRA mutations in the autoinhibited form | PDGFRA mutation # | exon 12 (V561D etc.) | <1% | Stomach>>small intestine | Epithelioid cell type Indolent clinical course in main | Probably sensitive to imatinib, sunitinib, regorafenib, ripretinib, avapritinib | |
exon 14 (N659K) | <1% | Probably sensitive to imatinib, sunitinib, regorafenib, ripretinib, avapritinib | |||||
exon 18 (del, Y849H etc., other than D842V) | 1–2% | Sensitive to imatinib, sunitinib, regorafenib, ripretinib, avapritinib | |||||
KIT or PDGFRA mutations in the activated form | PDGFRA exon 18 D842V, rarely KIT exon 17 D816V | ~10% | Stomach>>small intestine | Epithelioid cell type | D842V is resistant to imatinib, sunitinib, regorafenib. D842V is sensitive to avapritinib & ripretinib | ||
No mutation in KIT and PDGFRA | SDHB-competent | NF1 mutation $ | 1–2% | Small intestine | Spindle cell type Generally indolent clinical course associated with Neurofibromatosis type I | not sensitive to available drugs | possibly sensitive to MEK inhibitors, such as selumetinib |
BRAF mutation | <1% | Small intestine/stomach | Spindle cell type VE1-positive | possibly sensitive to BRAF inhibitors (e.g., vemurafenib, dabrafenib) | |||
HRAS, NRAS or KRAS mutation | very rare | no data | no data | MEK inhibitors (e.g., trametinib) may possibly have some activities | |||
Others including PIK3CA, CBL, ETV6–NTRK3 et al. | very rare | no data | no data | NTR-fusion is sensitive to entrectinib and larotrectinib | |||
SDHB-deficient | SDHA, SDHB, SDHC or SDHD mutation (including Carney-Stratakis syndrome #) | ~3% | Stomach>>small intestine | Epithelioid cell type SDHB-negative Children/adolescent and young adult Frequent lymph node metastasis Indolent clinical course | not sensitive to available drugs VEGFR inhibitors may have temporary stabilizing effects | ||
Loss of SDHB expression (including Carney Triad $) | <1% | Stomach |
Disease | Endoscopic Findings | EUS Findings | Pathological Features | |||
---|---|---|---|---|---|---|
Surface, Form, etc. | Major Location | Main Layer | Echo Findings | Morphology | IHC; Genetic Changes | |
GIST | hemi-spherical, occasionally with delle or ulcer | body | proper muscle, rarely submucosa | hypoechoic, heterogenous with increased malinancy | spindle cell > epithelioid cell | KIT, DOG1; mutation in KIT or PDGFRA |
Myogenic tumor & Leiomyoma | hemi-spherical, intact mucosa | near cardia | proper muscle, sometimes submucosa | round, hypoechoic, homogenous | spindle cell (eosinophilic cell) | Desmin, α-SMA |
Schwanomma & neurogenic tumor | hemi-spherical, intact mucosa | body, lesser curvature | proper muscle, sometimes submucosa~deep mucosa | hypoechoic, homogenous~slightly heterogeneous | spindle cell, palisading, Verocay body, lymphoid cuff in Schwannoma | S-100, SOX10, NSE in neurogenic tumor |
Heterotopic Pancreas | hill-shaped, intact mucosa, maybe dimple or aperture | antrum | submucosa | sometimes lobulated, ductal structure, heterogeneous internal echo, thickend proper muscle | Heimlich classification & | |
Neuroendocrine tumor | hemi-spherical, mucosal color~yellowish~red, occasionally dimple | body | initially deep mucosa or submucosa | homogenous, heterogeneous with increased malinancy | epithelioid cell, organoid pattern | CD56, synaptophysin, chromogranin A, NSE |
MALT lymphoma | various surface, multiple lesions | anywhere | deep mucosa~submucosa | beltlike~multiple round, hypoechoic, homogenous | Centrocyte-like, lymphoepithelial lesion, plasma cell differentiation | κ or λ chain; t(11;18)/API2-MALT1 |
Malignant lymphoma | various surface, multiple lesions | anywhere | initially deep mucosa~submucosa | beltlike~advanced carcinoma-like, hypoechoic, homogenous | CD20+, CD79a+; t(3;14)/BCL6-IGH | |
Lipoma & lipogenic tumor | hill-shaped to pedunculated, intact mucosa (~yellowish), cushion sign | antrum | submucosa | round~oval, hyperechoic | Lipoblast (spider-web cell) | MDM2, CDK4 in well differenciated liposarcoma |
Granular cell tumor | hemi-spherical, molar-like appearance, intact~ivoly | body | submucosa | round, heterogenously hypoechoic | eosinophilic granules | S-100, SOX10, CD68 |
inflammatory fibroid polyp (IFP) | pedunculated or penis-like, may with erosion/ulcer | antrum | deep mucosa~submucosa | hypoechoic, relatively homogeneous | perivascular fibrosis (onion skin pattern), eosinophil infiltration | CD34, α-SMA; mutations in PDGFRA |
inflammatory myofibroblastic tumor (IMT) | hill-shaped, mucosal color | fornix~body | hypoechoic (not definite) | spindle cell & inflammatory cell infiltration | ALK, α-SMA, ALK-fusion, CD34, | |
Solitary fibrous tumor (SFT) | n.d. | n.d. | n.d. | spindle cell, patternless pattern | CD34, nuclear STAT6, bcl2, CD99; NAB2-STAT6 fusion | |
Glomus tumor | hemi-spherical, same color as mucosa | antrum | proper muscle | relatively hyperechoic~heterogenous | eosinophilic cell with oval nucleus | α-SMA |
lymphangioma or cavenous hemangioma | flat-elavated, intact mucosa (whitish or dark-reddish, respectively), cushion sign | n.d. | deep mucosa~submucosa | aechoic~hyperechoic, multicystic | endothelial cells | CD31, CD34, Factor VIII in vascular tumor |
PEComa | hemi-spherical~polypoid, intact mucosa | n.d. | submucosa | hypoechoic, homogenous | epithelioid cell with clear cytoplasm | α-SMA, HMB45, Melan A; LOH of TSC2 |
Melanoma | pedunculated or lobular protrusion (may with melanosis), occasionally with erosion | n.d. | initially deep mucosa~submucosa | iso-hypoechoic, maybe regional lymph node metastasis | S-100, HMB45, Melan A, SOX10; mutations in BRAF ot KIT | |
Desmoid | n.d. | n.d. | n.d. | spindle cell | nuclear β-catenin; alterations in CTNNB1 | |
Metastatic tumor | bull’s eye~various, multiple lesions | n.d. | deep mucosa~submucosa | round~oval, hyperechoic & heterogenous |
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Nishida, T.; Yoshinaga, S.; Takahashi, T.; Naito, Y. Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors. Cancers 2021, 13, 3158. https://doi.org/10.3390/cancers13133158
Nishida T, Yoshinaga S, Takahashi T, Naito Y. Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors. Cancers. 2021; 13(13):3158. https://doi.org/10.3390/cancers13133158
Chicago/Turabian StyleNishida, Toshirou, Shigetaka Yoshinaga, Tsuyoshi Takahashi, and Yoichi Naito. 2021. "Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors" Cancers 13, no. 13: 3158. https://doi.org/10.3390/cancers13133158