INTRODUCTION
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors originating from the interstitial cells of Cajal in the gastrointestinal tract. Although the incidence of GISTs is relatively low, with approximately 10 cases per million people annually, the actual prevalence may be higher due to underdiagnosis and limited access to healthcare[1]. GISTs are primarily driven by mutations in the KIT proto-oncogene or the platelet-derived growth factor receptor alpha (PDGFRA) genes, which are critical for tumorigenesis[2,3]. A subset of GISTs, known as wild-type GISTs (wtGISTs), lack these mutations and may harbor other genetic alterations such as mutations in the succinate dehydrogenase (SDH) complex, neurofiber protein 1 (NF1) gene, BRAF, KRAS, PIK3CA mutations, and fusion genes[4,5].
The clinical presentation of GISTs is highly heterogeneous, ranging from asymptomatic to rapidly progressing disease, which poses significant diagnostic challenges. The age distribution of GIST patients peaks between 50 and 70 years[1]. Familial GISTs, though rare, exhibit unique clinical features such as earlier onset and multiple tumor occurrences, and are associated with genetic syndromes, such as primary familial GIST syndrome, Carney-Stratakis syndrome (CSS), and neurofibromatosis type 1 (NF-1)[6]. The management of GISTs has evolved significantly over the past decades. Initially, surgical resection was the primary treatment modality. However, the advent of tyrosine kinase inhibitors (TKIs) such as imatinib has revolutionized the treatment landscape, particularly for advanced and metastatic GISTs[7]. Despite the efficacy of TKIs, resistance, either primary or secondary, remains a major challenge, necessitating the development of novel therapeutic strategies. The molecular mechanisms underlying GISTs involve a variety of genetic mutations. Approximately 75%-80% of GISTs harbor KIT mutations, predominantly in exon 11, followed by exons 9, 13, and 17. PDGFRA mutations are present in about 10% of cases, mainly in exons 12 and 18. The presence of these mutations leads to constitutive activation of tyrosine kinases, driving uncontrolled cell proliferation and tumor growth[8,9]. The therapeutic landscape for GISTs continues to expand with the approval of new TKIs such as ripretinib and avapritinib, which target specific resistant mutations[10-13]. However, the optimal management of familial GISTs, including the timing and extent of surgical intervention and the role of genetic testing, remains to be fully elucidated.
In summary, GISTs are complex tumors with diverse genetic and clinical characteristics. The ongoing advancements in molecular diagnostics and targeted therapies hold promise for improving patient outcomes.
FAMILIAL GIST CLASSIFICATION AND CHARATERISTICS
Primary familial GIST
GIST with germline KIT or PDGFRA mutations is referred to as primary familial GIST[6,14]. The KIT gene encodes a transmembrane receptor tyrosine kinase, and mutations in this gene lead to abnormal activation of the receptor and continuous activation of downstream signaling pathways, such as PI3K/AKT, RAS/RAF/MEK/ERK, which are associated with cell proliferation, survival, and angiogenesis. The PDGFRA gene encodes the PDGFRA, also a tyrosine kinase receptor, and mutations cause structural changes in the receptor, leading to constitutive activation without the need for ligand binding. Activated PDGFRA receptors also activate downstream signaling pathways, promoting cell proliferation and inhibiting apoptosis, ultimately leading to tumor formation[8,15,16]. Primary familial GIST is characterized by an early age of onset and multifocality. In addition to GIST, patients with germline KIT mutations may have associated conditions such as hyperpigmentation, dysphagia, and mast cell disease, while those with PDGFRA mutations may have inflammatory fibroid polyps, uterine leiomyomas, and macrodactyly[6].
NF-1-associated GIST
NF-1, also known as von Recklinghausen disease, is caused by mutations in the NF1 gene, which encodes neurofibromin, a tumor suppressor protein[17]. Mutations in the NF1 gene result in the loss of neurofibromin function, enhancing the GTPase activity of RAS proteins and leading to the sustained activation of the RAS/RAF/MEK/ERK (MAPK) signaling pathway, promoting the proliferation of mesenchymal cells and tumor formation[18,19]. NF-1-associated GISTs typically occur in young females and are more common in the small intestine compared to sporadic GISTs, also characterized by multifocality. The clinical manifestations are characterized by multi-system involvement, including the skin (cafe-au-lait macules, cutaneous neurofibromas), nervous system (learning disabilities and cognitive issues), and skeletal system (skeletal deformities). Some NF-1-associated GISTs may be asymptomatic or present with nonspecific symptoms such as abdominal pain or gastrointestinal bleeding, leading to potential diagnostic delays[20]. In most patients studied or observed clinically, no mutations were found in the common mutation hotspots of KIT and PDGFRA genes of GISTs[17].
SDH-deficient GIST
SDH-deficient GIST may be part of different genetic syndromes, commonly seen in CSS, while Carney Triad (CT) is rare. The pathogenesis of SDH-deficient GIST involves metabolic abnormalities, increased oxidative stress, DNA repair defects, and imbalances in cell proliferation and apoptosis due to the loss of SDH complex function. These mechanisms lead to the occurrence and development of tumors and may affect patients' treatment options and prognosis[21]. CSS, also known as the dyad of GIST and paragangliomas, has a roughly equal incidence in males and females and is associated with germline mutations in SDH genes, inherited in an autosomal dominant pattern. CT includes GISTs, pulmonary chondromas, and paragangliomas, usually diagnosed in young females, and unlike CSS, is not generally considered hereditary, although some cases may exhibit familial aggregation[22,23]. Diagnosis may be made based on the symptoms from any of the tumors in the triad, depending on the type, size, and location of the tumor. For example, GIST may be discovered due to bleeding or obstruction, pulmonary chondromas may be asymptomatic or cause respiratory problems, and paragangliomas may lead to hypertension due to abnormal hormone secretion. SDH-deficient GISTs almost always occur in the stomach and exhibit characteristics of multifocality, early lymphatic and vascular invasion, and lymph node metastasis[23].
Wang et al[24] reported two rare cases within the same family where two patients had different mutation types of familial GIST (one patient with a mutation in exon 12 of the PDGFRA gene, considered primary familial GIST, and the other patient with an unspecified mutation gene wtGIST). Both primary familial GIST and wtGIST are rare diseases, and both occurring within the same family lineage has not been reported, highlighting the complexity and heterogeneity of GIST. However, there have been previous case reports of multiple different genetic mutation types of GIST within the same patient[1,17]. The genetic susceptibility observed in familial GISTs provides valuable insights into the genetic aspects of these tumors. The presence of multiple different genetic mutation types in the same patient or family emphasizes the importance of comprehensive genetic testing and personalized treatment strategies. However, the patients in their report did not undergo comprehensive genetic testing. Incomplete diagnosis may add more uncertainty and financial pressure to the subsequent treatment of patients. We suggest that patients with familial stromal tumors should undergo comprehensive genetic testing so as to develop personalized treatment strategies and the impact of these genetic variations on treatment response and prognosis should be evaluated. In addition, during the follow-up period, specialists in genetics and molecular biology can be included in the multidisciplinary team to ensure a thorough exploration and understanding of the genetic aspects.
TREATMENT AND MANAGEMENT STRATEGIES
At present, surgical resection remains the only effective therapeutic intervention, and the role of surgery in advanced GIST and wild-type stromal tumors is controversial[25]. Some scholars believe that surgical treatment may be helpful for patients who respond to adjuvant therapy, those with limited local progression, and those undergoing palliative treatment. Many studies have shown that wild-type stromal tumors are often indolent, with patients living long-term as the tumor progresses slowly, and they have a good median survival of about 10 years, early surgery seems less important[26,27]. With the increase in case reports, some scholars have found that NF-1 related GIST, when metastasis occurs, has a very poor prognosis, with a survival not exceeding 2 years, and surgical treatment can improve the patient's prognosis and reduce the long-term risk of death[28]. In patients with other serious clinical symptoms, such as gastrointestinal bleeding, obstruction, pain, to control limited lesions, surgical treatment is also supported, and surgical resection can also help to clarify the molecular pathological characteristics of the tumor, and the risk level to guide later treatment and monitoring[17,23,29]. Considering the multifocality of familial GIST, complete surgical resection may be challenging, and the risk of recurrence is still high. Therefore, it is usually necessary to combine surgery with systemic treatment to achieve the best outcome. For metastatic or recurrent GIST, the first-line treatment drug is the tyrosine kinase inhibitor imatinib mesylate (IM), which is also used for neoadjuvant and adjuvant treatment of localized GIST. Imatinib is usually well-tolerated, and the most common adverse reactions are rash, nausea, diarrhea, and fluid retention, especially periorbital edema. Few patients (< 1%) have serious adverse reactions. The types of GIST associated with primary imatinib resistance include PDGFRA exon 18 D842V mutation or GIST types without KIT or PDGFRA mutations[1,30,31]. In fact, with the discovery of more and more wtGIST cases, it has been found that the use of imatinib can also achieve certain therapeutic effects. The reason may lie in the technical errors of gene testing that missed KIT/PDGFRA mutations[32]. Most evidence shows that imatinib is not very beneficial for wtGIST patients, and these patients should be observed or try second-line or third-line drug treatment after local tumor resection, such as sunitinib, regorafenib therapy[1,7]. Of course, there are still many other drugs in clinical trials that have also shown good efficacy, hoping to improve the prognosis of advanced GIST and wtGIST patients.
For patients with GIST due to mutations in the 12th exon of the PDGFRA gene (primary familial GIST), imatinib is usually effective[32]. We believe that the treatment and monitoring of primary familial GIST with surgery combined with imatinib reported by Wang et al[24] and others is reasonable. There is not much evidence to support the use of imatinib as adjuvant therapy after surgery for wtGIST patient, but the patient in their report has now stopped imatinib treatment and is being followed up. It is necessary to supplement gene testing for this patient to guide subsequent treatment. Due to the rarity of familial stromal tumors, there is insufficient long-term follow-up data for surgery and targeted treatment, and there is currently no sufficient evidence to guide the choice of treatment plan, the duration of drug use, the best follow-up monitoring method, and the review frequency all require additional prospective work. In our opinion, in the case of this wtGIST patient where the gene mutation is not clearly identified, there is no need for adjuvant drug therapy after surgery (especially since imatinib is usually resistant to wtGIST). In addition, a comprehensive multidisciplinary team assessment should be performed regarding the treatment and post-surgical management. This team approach can help tailor treatment plans based on the specific genetic and clinical characteristics of each patient. At the same time, clinicians should be aware that patients with familial GISTs may have a higher risk of developing other tumors. Patients with primary familial GISTs are prone to have other tumors such as breast cancer and papillary thyroid cancer, while hereditary syndromes associated with wtGISTs will have other tumors[6,17,27]. It remains to be determined whether long-term TKI treatment or frequent imaging examinations will further increase the risk of developing a second malignant tumor in this population, but for patients with familial stromal tumors, imaging monitoring is necessary. In addition, the improvement of gene testing is indispensable in diagnosis, treatment, and follow-up. Physicians should recommend that patients with familial GIST undergo early genetic counseling to help with prenatal gene diagnosis or assisted reproductive technology to reduce the possibility of passing on pathogenic gene mutations to offspring.
CONCLUSION
There is still little evidence for the treatment, prognosis, and monitoring of familial GISTs, and there are no unified guidelines and plans. The general treatment rules are the same as those for sporadic GISTs. The management of GISTs, especially familial cases, requires a multidisciplinary approach. We suggest that clinicians should be aware of the possibility of other clinical features and tumor screening when discovering multifocal GIST, and incorporate gene testing into routine clinical practice. It is crucial for the early identification of high-risk individuals and the implementation of tailored monitoring programs. A more aggressive treatment approach is recommended, including surgery and the use of drugs based on gene testing, and the follow-up strategy suggests personalized, multidisciplinary, and lifelong management for patients and their family members. With the advancement of molecular genetics and targeted therapy, the future of familial gastrointestinal stromal tumor management is expected to provide more effective and personalized treatment methods, ultimately improving the prognosis and quality of life for patients with this challenging disease.
