RECKGIST is an appropriate relapse risk scoring system for gastrointestinal stromal tumors in patients with neurofibromatosis

Recently, Cuvelier et al. published the results of a large French cohort study investigating gastrointestinal stromal tumors (GISTs) associated with neurofibromatosis type 1 (NF1) (1). Cuvelier et al. propose a distinct relapse risk for GISTs in individuals with NF1 compared to the general population. They named this the RECKGIST score, which enables healthcare providers to recognize the lower risk in people with NF1 (1). This commentary provides background to support their research.

GISTs are rare tumors of the digestive tract that most often develop in the stomach or small intestine (2). While usually sporadic, they may be linked to genetic conditions such as NF1. NF1 is a genetic disorder causing tumors on nerve tissue, skin changes and increased cancer risk. GISTs associated with NF1 have distinct clinical features to sporadic GISTs (3). Sporadic GISTs typically present in the 60 s, whereas NF1-associated GISTs present in the 50 s. They are slightly more prevalent in women. NF1-associated GISTs are often discovered incidentally (4). Bleeding, anemia, abdominal pain and intestinal obstruction are not uncommon. NF1-associated GISTs are primarily located in the small intestine (89% in one study and 86% in another) (4-6) followed by the stomach (5% in one study and 11% in another) (4-6) in contrast to sporadic GISTs, which most commonly present in the stomach (60–70%), with 20–30% located in the small intestine (7). NF1-associated GISTs show a small primary tumor size (6). Multiple GISTs were common (6). NF1-associated GISTs typically have lower mitotic activity than sporadic GISTs, contributing to their indolent behavior. A large French cohort study reported that 79% of cases had ≤5 mitoses/50 high-power field (HPF), classifying most as low risk, whereas high mitotic counts (>5/50 HPF) were seen in only ~20% of cases (1). In another large cohort study, the mean mitotic rate is ~3/50 HPF (5). Mitotic counts in sporadic GISTs are variable and sporadic GISTs are more likely to present with intermediate/high-risk mitotic counts, contributing to their higher overall aggressiveness (8). NF1-associated GISTs are genetically distinct from sporadic GISTs. Biallelic inactivation of the NF1 tumor suppressor gene (chromosome 17q11.2) is central, leading to loss of neurofibromin and constitutive activation of the RAS/RAF/MAPK pathway (9). Somatic mutations or loss of heterozygosity (LOH) in NF1 are common, often through mitotic recombination (9). Unlike sporadic GISTs, NF1-associated tumors typically lack KIT or PDGFRA mutations (>95% are wild-type). KIT or PDGFRA mutations can occur in a small percentage of NF1-GISTs and may be associated with higher recurrence risk in this subgroup (1). In contrast, KIT/PDGFRA mutations are common in sporadic GISTs (80–90%) (9) (Table 1).

Complete surgical resection remains the primary treatment for localized GIST, and adjuvant imatinib therapy has been shown to benefit high-risk patients. An accurate risk assessment is crucial for guiding decisions about adjuvant therapy after surgical resection. The risk of recurrence in GISTs is assessed using various classification systems, such as the National Institutes of Health (NIH) consensus criteria, the Armed Forces Institute of Pathology (AFIP) criteria and the modified NIH criteria. The NIH consensus criteria (also known as the Fletcher criteria), developed in 2002, classify risk as very low, low, intermediate, or high based on tumor size and mitotic count (per 50 HPF). Since then, Miettinen and Lasotta refined the risk tables based on follow-up information from over 1,900 GIST patients. They noted the proportion of patients who actually developed recurrence or metastasis according to tumor location, size, and mitotic count (8). These AFIP criteria (often called the Miettinen-Lasota criteria) incorporate tumor size, mitotic count, and tumor site as important risk factors. GISTs arising from the stomach generally have a better prognosis than those arising from the small bowel or rectum (8). DeMatteo et al. evaluated data from 127 patients with primary GIST and confirmed the AFIP finding that tumor location is an independent prognostic factor alongside tumor size and mitotic rate (12). Goh et al. noted that even within the AFIP high-risk group, recurrence rates vary widely. They demonstrated a very high-risk group, defined as tumors greater than 10 cm in size with a mitotic count greater than >5/50 HPF, and had poor patient outcomes. Patients with a mitotic count greater than >5/50 HPF had fewer recurrences than patients with tumors between 5 and 10 cm in size (13). Modified NIH criteria (Joensuu criteria) typically consider four factors: tumor size, mitotic count, tumor location (gastric vs. non-gastric), and tumor rupture (present or absent) (14). The National Comprehensive Cancer Network (NCCN) GIST Task Force adopted the Miettinen and Lasota reports, based on the risk classification on tumor location, size, and mitotic count (15). In addition to major prognostic factors, comprehensive prognostic factors include the Ki-67 index and genetic factors. Mutational analysis, including KIT, PDGFRA and SDH mutations, is useful for classifying GISTs, and for guiding personalized therapy with tyrosine kinase inhibitors. Systemic therapy agents for advanced GIST include imatinib, sunitinib, regorafenib and ripretinib (16). Adjuvant imatinib is recommended for high-risk GISTs with imatinib-sensitive mutations. Avapritinib is preferred for GISTs with PDGFRA exon 18 mutations that are insensitive to imatinib (16).

According to the modified NIH system, low-risk GISTs are generally defined as tumors of any size, originating from any site, with a mitotic index of ≤5 mitoses/50 HPF (14). Low-risk GISTs typically have a favorable outcome and generally do not require adjuvant therapy. However, even among patients with low-risk GISTs, a small proportion can experience recurrence or metastasis following surgical removal. A study investigated factors associated with postoperative recurrence or metastasis in low-risk GIST (5). Multivariate analysis identified the primary tumor site, tumor size, and Ki-67 index as independent risk factors for postoperative recurrence and metastasis. Primary tumors in non-gastric sites (e.g., the small intestine or rectum) and larger tumors within the low-risk size range (2–5 cm) were also associated with a higher risk of recurrence. The study suggested that tumors larger than a cutoff value of 4.0 cm were significantly associated with recurrence. Patients with a Ki-67 index of >5% were found to have significantly worse outcomes than those with a Ki-67 index of ≤5% (5).

NF1-associated GISTs have distinct clinical features and require specific prognostic evaluation. Standard risk classification systems may not accurately predict relapses in these tumors. Recently, Cuvelier et al. reported that NF1-GISTs are typically indolent with favorable outcomes, especially for tumors ≤3 cm (near-zero recurrence), in a large French cohort study of NF1-GIST. The 5-year survival rate for NF1-associated GISTs was 92%, which is higher than the survival rate for sporadic GISTs. The 10-year recurrence-free survival (RFS) rate was approximately 82.5%, and the 15-year rate was 65.1%. However, rare KIT/PDGFRA-mutant subsets or large/high-mitotic tumors behave more aggressively. For tumors >30 mm, the risk of recurrence rises sharply if there are more than 5 mitoses/50 HPF (10-year RFS drops to 43.2% vs. 79.8% for lower counts) (1). KIT or PDGFRA mutations can occur in a small percentage of NF1-GISTs and may be associated with higher recurrence risk in this subgroup. Based on those results, they proposed a new prognostic score (RECKGIST) for NF1-GISTs, which is based on tumor size and mitotic count.

• Score A: tumor ≤30 mm—no recurrence observed;
• Score B: tumor >30 mm and ≤5 mitoses/50 HPF;
• Score C: tumor >30 mm and >5 mitoses/50 HPF—highest recurrence risk.

NF1-associated GISTs represent a distinct subset requiring specific considerations for risk assessment due to their unique clinical and molecular features. The development of specialized prognostic tools like the RECKGIST score for NF1-GISTs underscores the importance of tailoring risk evaluation to specific GIST subtypes (15).

Acknowledgments

None.

Footnote

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