Guidelines Summary

WHO Classification of Tumors

In 2013 the World Health Organization released an update of its 2002 classification system for tumors of the soft tissue and bone. The update incorporated more detailed cytogenetic and molecular data into the classifications. Gastrointestinal stromal tumors (GISTs) have been added in the update, with three subtypes^[82]:

Benign
Uncertain malignant potential
Malignant

Tumor Grading Systems

The French Federation of Cancer Centers Sarcoma Group (FNCLCC) system ^[83]and the National Cancer Institute system are most commonly used for grading soft tissue sarcomas.^[84] Both are three-grade systems. The FNCLCC is based on tumor differentiation, tumor necrosis and mitotic activity, while the NCI system bases the evaluation on histology, location and tumor necrosis. In comparison studies, the FNCLCC has shown slightly better ability to predict metastasis development and mortality.

The American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) grades GISTs separately from other sarcomas, using a two-grade system based on mitotic rate, as follows^[39]:

Low: ≤5 mitoses per 5 mm ², or per 50 high-power field (HPF)
High: > 5 mitoses per 5 mm ², or per 50 HPF

Tumor Staging

For staging of GISTs, both the NCCN and the European Society for Medical Oncology (ESMO) guidelines follow the tumor-node-metastasis (TNM) classification of the AJCC/UICC. Anatomic stage/prognostic groupings for GIST are detailed in Table 4, below.^[51]

Table 4. Staging of Gastric Gastrointestinal Stromal Tumors (Open Table in a new window)

Stage	T	N	M	Grade
IA	T1 or T2	N0	M0	Low
IB	T3	N0	M0	Low
II	T1	N0	M0	High
	T2	N0	M0	High
	T4	N0	M0	Low
IIIA	T3	N0	M0	High
IIIB	T4	N0	M0	High
IV	Any T	N1	M0	Any grade
IV	Any T	Any N	M1	Any grade

For description of GIST TNM designations, see Gastrointestinal Stromal Tumors Staging.

Diagnosis

The NCCN guidelines for GISTs recommend evaluation and management, prior to initiation of therapy, by a multidisciplinary team with expertise and experience in sarcoma. Abdominal/pelvic CT scan with contrast, with or without MRI, is also indicated and chest imaging should be considered. Very small gastric GISTs (< 2 cm) may be evaluated with endoscopic ultrasound-guided fine-needle aspiration; for GISTs 2 cm or larger, endoscopy with or without ultrasound may also be indicated in select patients.^[39]

Genetic testing for KIT and PDGFRA is a strong recommendation when medical therapy is being considered. Identification of certain specific KIT and PDGFRA mutations helps predict responsiveness to imatinib and the possible benefit of a higher imatinib dose.

In patients with GISTs that lack KIT or PDGFRA mutations, immunohistochemistry (IHC) for SDHB deficiency, for gastric tumors, and succinate dehydrogenase (SDH) mutation testing for SDHB-deficient tumors is indicated. Germline loss-of-function mutations within the SDH gene subunits SDHB, SDHC, and SDHD have been identified in individuals with GISTs associated with Carney-Stratakis syndrome, an autosomal dominant familial syndrome characterized by a predisposition to GISTs and paragangliomas. In addition, next-generation sequencing (NGS) testing for alternative driver mutations (eg, BRAF, NF1, NTRK, and FGFR fusions) should be performed, as it may identify tumors that could respond to targeted therapy.^[39]

Treatment

NCCN treatment recommendations for localized resectable disease include the following^[39]:

Surgical resection is recommended for gastric tumors < 2 cm with no high-risk features (eg, irregular border, cystic spaces, ulceration, echogenic foci, heterogeneity) and for known or suspected GISTs that are resectable with minimal morbidity.
Consider periodic endoscopic or radiographic surveillance for gastric GISTs < 2 cm with no high-risk features.
For GISTs that are resectable but with significant morbidity, consider neoadjuvant imatinib, or avapritinib for GISTs with PDGFRA exon 18 mutations that produce insensitivity to imatinib (eg, the D842V mutation). Follow with surgery if feasible.
After complete resection, treat with adjuvant imatinib in patients at intermediate or high risk of recurrence; continue imatinib in patients who received it preoperatively.
Follow with history and physical and abdominal/pelvic CT every 3-6 months for 5 years, then annually.

ESMO guidelines recommend that patients with small esophagogastric or duodenal nodules < 2 cm undergo endoscopic ultrasound assessment and then annual follow-up, reserving excision for patients whose tumor increases in size or becomes symptomatic. For small rectal nodules, however, the ESMO guidelines recommend biopsy/excision after ultrasound assessment, regardless of tumor size. In addition, all nodules 2 cm or larger require biopsy. ESMO guidelines discourage a laparoscopic approach for resection of large tumors.^[25]

The NCCN recommends tyrosine kinase inhibitor (TKI) therapy for unresectable, recurrent, or metastatic disease, as follows (all category 1)^[39]:

Imatinib
After assessment of therapeutic effect, resection may be considered or imatinib may be continued if resection is not feasible
Sunitinib for patients with imatinib-resistant GIST
Regorafenib for patients with disease progression on imatinib and sunitinib
Ripretinib for patients with disease progression on imatinib, sunitinib, and regorafenib
TKI therapy should be continued as long as patients experience clinical benefit (response or stable disease)
Continuation of TKI therapy lifelong for palliation of symptoms is an essential component of best supportive care

Medication

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Media Gallery

Shown here is a gastric gastrointestinal stromal tumor (GIST). This is a gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration.
CT scan of the abdomen with oral contrast in a 60-year-old woman with a gastric gastrointestinal stromal tumor (GIST). A huge mass with central necrosis is observed originating from the gastric wall and narrowing its lumen. An ulcer crater can be identified within the mass (arrow).
Photomicrograph of gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 40X. Note the solid sheet of spindle cells.
Photomicrograph of gastric gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 400X. This stromal tumor demonstrates spindle cells with epithelioid features.
Photomicrograph of gastrointestinal stromal tumor (GIST) with immunohistochemical staining for CD117. Note the strong positive staining of tumor cells with negative staining of the adjacent vessel. Positive stain for CD117 is diagnostic of GIST.

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Table 1. TNM Classification for Gastrointestinal Stromal Tumors

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor 2 cm or smaller
T2	Tumor more than 2 cm but not more than 5 cm
T3	Tumor more than 5 but not more than 10 cm
T4	Tumor more than 10 cm in greatest dimension
Regional lymph node (N)
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis
Metastasis (M)
M0	No distant metastasis
M1	Distant metastases

Table 2. Anatomic Stage/Prognostic Groups for Gastric GISTs

Group	Tumor	Node	Metastasis	Mitotic Rate*
Stage IA	T1 or T2	N0	M0	Low
Stage IB	T3	N0	M0	Low
Stage II	T1	N0	M0	High
	T2	N0	M0	High
	T4	N0	M0	Low
Stage IIIA	T3	N0	M0	High
Stage IIIB	T4	N0	M0	High
Stage IV	Any T	N1	M0	Any rate
Stage IV	Any T	Any N	M1	Any rate
*Mitotic rate: Low (≤5 per 5 mm² or per 50 HPF); High (>5 per 5 mm² or per 50 HPF)

Table 3. Anatomic Stage/Prognostic Groups for Small-Intestinal GISTs

Group	Tumor	Node	Metastasis	Mitotic Rate*
Stage I	T1 or T2	N0	M0	Low
Stage II	T3	N0	M0	Low
Stage IIIA	T1	N0	M0	High
Stage IIIA	T4	N0	M0	Low
Stage IIIB	T2	N0	M0	High
	T3	N0	M0	High
	T4	N0	M0	High
Stage IV	Any T	N1	M0	Any Rate
Stage IV	Any T	Any N	M1	Any Rate
*Mitotic rate: Low (≤5 per 5 mm² or per 50 HPF); High (>5 per 5 mm² or per 50 HPF)

Table 4. Malignant Potential of Gastric GISTs (NCCN)

Tumor Size	Mitotic Rate*	Predicted Metastasis Rate
≤2 cm	Any mitotic rate	0%
>2 to 5 cm	≤5	1.9%
>2 to 5 cm	>5	16%
>5 to 10 cm	≤5	3.6%
>5 to 10 cm	>5	55%
>10 cm	≤5	12%
>10 cm	>5	86%
*Number of metastases per 5 mm² or per 50 high-power field

Table 5. Malignant Potential of Non-Gastric GISTs (NCCN)

Tumor Size	Mitotic Rate*	Predicted Metastasis Rate
≤2 cm	≤5	0%
≤2 cm	>5	50-54%
>2 to 5 cm	≤5	1.9-8.5%
>2 to 5 cm	>5	50-73%
>5 to 10 cm	≤5	24%
>5 to 10 cm	>5	85%
>10 cm	≤5	34-52%
>10 cm	>5	71-90%
*Number of metastases per 5 mm² or per 50 high-power field

Table 4. Staging of Gastric Gastrointestinal Stromal Tumors

Stage	T	N	M	Grade
IA	T1 or T2	N0	M0	Low
IB	T3	N0	M0	Low
II	T1	N0	M0	High
	T2	N0	M0	High
	T4	N0	M0	Low
IIIA	T3	N0	M0	High
IIIB	T4	N0	M0	High
IV	Any T	N1	M0	Any grade
IV	Any T	Any N	M1	Any grade