Two different mutational types of familial gastrointestinal stromal tumors: Two case reports

Abstract

BACKGROUND

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and cases of GISTs tend to be of the disseminated type, with a global incidence of 10 to 15 cases/million each year. The rarer familial GISTs, which often represent a population, differ in screening, diagnosis, and treatment. Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs. However, whether the same genetic family has different phenotypes has not been reported.

CASE SUMMARY

We report two cases of rare GISTs in the same family: A male patient with the V561D mutation in exon 12 of the PDGFRA gene, who has been taking the targeted drug imatinib since undergoing surgery, and a female patient diagnosed with wild-type GIST, who has been taking imatinib for 3 years since undergoing surgery. The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy, and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease.

CONCLUSION

Different mutation types of familial GISTs in the same family are very rare, thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.

Key Words: Gastrointestinal stromal tumor; Familial gastrointestinal stromal tumor; Wild-type gastrointestinal stromal tumors; PDGFRA; Imatinib; Treatment; Case report

Core Tip: Familial gastrointestinal stromal tumors (GISTs) include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs; however, there are no reports on whether there are different types of GISTs in the same genetic family. We report two cases of GISTs in the same family with different types of mutations. During our long-term follow-up, the favorable prognosis of these patients verified the accuracy of our treatment strategy. We also improved the whole process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease.

INTRODUCTION

Gastrointestinal stromal tumors (GISTs), are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and originate from GI pacemaker cells [interstitial cells of Cajal (ICC)] or related stem cells[1]. The biological behavior of GISTs range from benign to malignant, with an incidence rate of 10-15 cases/million each year globally, and they are seen predominantly in middle-aged and elderly people, with the median age of onset being in the 60 years, and with an even distribution in males and females[2]. Tumor sites are most commonly found in the stomach (60%-70%), followed by the small intestine (20%-25%), colon and rectum (5%), and esophagus (< 5%)[3]. The majority of GISTs are caused by KIT mutations (present in 75%-80% of cases) and platelet-derived growth factor receptor A (PDGFRA) mutations (present in approximately 10% of cases)[4], with the remaining 10%-15% of GISTs being referred to as wild-type (wt) GISTs. In GISTs, KIT and PDGFRA mutations are mutually exclusive[5], with KIT mutations generally clustered in exons 11 and 9, while PDGFRA mutations are generally clustered in exons 12, 14 and 18[6]. Targeted chemotherapy based on the relevant mutation sites of KIT/PDGFRA has become essential for the treatment of patients with GISTs.

Familial GISTs mainly include primary familial GISTs with predominantly KIT/PDGFRA mutations and wtGISTs, of which wtGISTs with predominantly succinate dehydrogenase complex subunit B (SDHB) defects can be divided into SDHB-deficient and non-SDHB-deficient types. The former includes Carney-Stratakis syndrome (CSS), Carney triad, SDHA mutation and some disseminated GISTs, and the latter includes neurofibromatosis type 1 (NF1)-associated, BRAF mutant, KRAS-mutant, and quadruple wtGISTs (without SDH, NF1, BRAF, and RAS-associated mutations)[7-10] (Figure 1). Among them, the SDHB-deficient type is generally prevalent in young women (37 ± 14 years old), presenting as lobar and/or multifocal tumors in the gastric portion, which usually have a slow clinical course and are often accompanied by lymph node metastasis[11]. It has been demonstrated that negative SDHB immunohistochemical staining (SDHB^IHC-) is of great significance in the diagnosis of CSS and Carney’s triad, and diagnosis of the first two conditions should be preferred if SDHB immunostaining is not present in GISTs[12]. SDHB^IHC- GIST occurs in young patients, mostly in the stomach, with unremarkable clinical symptoms, and patients have a better overall survival (OS); whereas NF1-GIST generally involves the small intestine and presents as a multifocal spindle cell tumor[11].

Figure 1 Familial gastrointestinal stromal tumor classification. GISTs: Gastrointestinal stromal tumors; wtGISTs: Wild-type Gastrointestinal stromal tumors; SDHB: Succinate dehydrogenase complex subunit B; IHC: Immunohistochemical staining.

Most GISTs are sporadic and only about 5% of patients with GISTs have one of the familial GISTs syndromes, and sporadic cases of GISTs are indistinguishable from familial GISTs on phenotypic, histologic or molecular grounds alone[13]. However, compared to sporadic GISTs, familial GISTs usually present as multifocal tumors and have an earlier age of onset (40-50 years)[7], as in the female patient in the present study, who presented with multifocal lesions in the stomach and showed different risk grades. In addition, familial GISTs have specific clinical manifestations such as skin pigmentation, mastocytosis, large hands and inflammatory fibrous polyps in addition to common symptoms such as GI bleeding, abdominal distension and abdominal pain[13]; however, the above mentioned manifestations were not demonstrated in our two patients. Here, we report two cases of familial GISTs in a multitumor family (Figure 2), in which the first patient was diagnosed with gastric lesions with multiple wtGISTs (II-2), and following our investigation of the patient’s family history, her younger brother was also diagnosed with GIST (II-4) in the presence of the PDGFRA (V561D) mutation one year earlier (Figure 2). Both patients received adjuvant therapy with imatinib after surgical resection of the tumor and had a good prognosis.

Figure 2 The family pedigree. Square: Male; round: Female; GISTs: Gastrointestinal stromal tumors; wtGISTs: Wild-type Gastrointestinal stromal tumors.

CASE PRESENTATION

Chief complaints

A 61-year-old female patient (elder sister) was admitted to hospital for 3 months due to intermittent abdominal pain and abdominal distension for 2 years and aggravation with loss of appetite. The 49-year-old male patient (younger brother) was admitted to hospital mainly due to intermittent abdominal distension, diarrhea with black stool for more than 3 months, and aggravation with vomiting for 2 weeks.

History of present illness

After admission, both patients were examined by electronic gastroscopy and protruding lesions in the gastric mucosa were observed (Figure 3).

Figure 3 Preoperative gastroscopy results of both patients. A: A submucosal lesion in the stomach body; B: A mucosal lesion approximately 1.5 cm × 2.0 cm in the fundus of the stomach.

History of past illness

Both patients had no other relevant medical history.

Personal and family history

Both patients denied a family history of other malignant tumors.

Physical examination

Physical examinations showed no significant abnormalities and vital signs were stable in both patients.

Laboratory examinations

Serum tumor markers including carcinoembryonic antigen, cancer antigen (CA) 199, CA125, CA724, and CA153 were within the normal range in both patients.

Imaging examinations

Endoscopic ultrasonography findings in the male patient showed the presence of an elevated hypoechoic mucosal lesion originating from the lamina propria on the greater curvature side of the gastric body, with a hyperechoic nodule visible in the center, measuring 3.0 cm × 2.0 cm, with a cross-sectional size of 21.6 mm × 18.7 mm.

Further diagnostic work-up

Postoperative histopathological examination of tumor tissue from the male patient showed that the tumor was composed of fusiform cells with a fasciculate arrangement (Figure 4A). The tumor locally invaded the submucosa and lamina propria, and no abnormalities were found in the mucosal layer. Immunohistochemical staining showed that KIT/CD117 (Figure 4B), DOG-1 (Figure 4C) and CD34 were positive (Figure 4D), and the Ki-67 index was 8%-10%. GIST was diagnosed by pathological examination, and the risk grade was high (nuclear fission image: 18/50 HPF). The results of gene detection showed that there was a V561D mutation in exon 12 of the PDGFRA gene (Figure 5).

Figure 4 Histopathological and immunohistochemical examination of the lesions. A: The lesions were stained with hematoxylin and eosin (H&E), revealing spindle-shaped cells arranged in bundles; B: KIT/CD117 showed positive immune responses; C: DOG1 showed positive immune responses; D: CD34 showed positive immune responses; E: The lesions were stained with H&E, revealing spindle-shaped cells arranged in bundles; F: KIT/CD117 showed positive immune responses; G: DOG1 showed positive immune responses; H: CD34 showed positive immune responses (original magnification, × 40).

Figure 5 The results of gene detection in the male patient. The excised lesion showed the presence of V561D mutation in exon 12 of the PDGFRA gene. The GTC to GAC conversion occurred at codon 561. TM: Transmembrane domain; JM: Intracellular juxtamembrane domain; PDGF: Platelet-derived growth factor.

Postoperative histopathological examination of tissue from the female patient showed that there were two lesions, tumor 1: Size 0.8 cm × 0.8 cm × 0.8 cm, nuclear fission picture: < 5/50 HPF, very low risk; tumor 2: Size 1.5 cm × 1.5 cm × 1.5 cm, nuclear fission image: 6/50 HPF, moderate risk. The tumor tissues were composed of spindle cells with uneven density, arranged in bundles or weaves, and the nuclei were oval or rod-shaped (Figure 4E). Immunohistochemical staining showed that KIT/CD117 (Figure 4F), DOG-1 (Figure 4G) and CD34 were diffusely positive (Figure 4H) and the Ki-67 index was 5%. The results of gene detection showed no KIT/PDGFRA mutation, and that the tumors were wtGISTs.

FINAL DIAGNOSIS

According to the clinical manifestations and imaging findings, both patients were eventually diagnosed with GISTs.

TREATMENT

According to the genetic test results of both patients, the male patient received treatment with oral imatinib 400 mg/day and was followed up every 3 months until now. The female patient received treatment with oral imatinib 400 mg/day and was followed up every 3 months for three years.

OUTCOME AND FOLLOW-UP

According to our recent follow-up results, both patients had a good prognosis and there was no recurrence or metastasis observed (Figure 6).

Figure 6 Postoperative follow-up examination results in September 2023. Comparison of pre- and postoperative computed tomography (CT) images of the male patient. A: Preoperative CT plain scan of the whole abdomen with localized nodular shadows in the antrum of the stomach; B: Postoperative CT plain scan of the whole abdomen with postoperative changes in the distal stomach and no abnormal signs in the anastomosis; C: Gastrointestinal ultrasonography showing postoperative gastrointestinal stromal tumor, with no space-occupying lesions inside or outside the gastric lumen; D: Postoperative CT of the female patient showing postoperative changes after partial resection of the gastric fundus with no abnormal signs in the anastomosis.

DISCUSSION

In the study of familial GISTs, not only activation of KIT or PDGFRA mutations, but possibly other genetic changes are required during the development of GISTs from polyclonal proliferation of diffuse ICC to monoclonal ones[14]. At the structural level, PDGFRA and KIT belong to the same receptor tyrosine kinase (RTK) subfamily, and at the functional level, PDGFRA and KIT mutations lead to the same biological consequences during tumor progression, e.g., leading to the activation of common pathways such as the PI3K/AKT anti-apoptotic pathway, the JAK/STAT3 transcriptional pathway, and the Ras/MAPK mitotic pathway. Response to analogs such as imatinib, demonstrates that PDGFRA is likely to be the second familial GIST susceptibility gene after KIT[8,15,16]. Mutations in exon 18, followed by exon 12, are the most common mutations in the PDGFRA gene, and only one type of mutation, the V561D mutation in exon 12, is known[17].

A total of 54 cases of familial GISTs have been reported to date, of which 49 cases described hereditary GISTs due to germline KIT mutations, 6 cases described familial GISTs associated with germline PDGFRA mutations, and only 1 case of V561D mutation in exon 12 of the PDGFRA gene has been reported in relation to the present case[8]. KIT and PDGFRA are both homologous type III RTKs consisting of five immunoglobulin (Ig)-like structural domains, i.e., ligand-binding extracellular, transmembrane, intracellular juxtamembrane (JM), and two TK structural domains[18], of which the V561D missense mutation is the most common mutation in the PDGFRA JM structural domain[19]. It has been shown that deletions in chromosomal regions 1p33-36, 9q12-24, 11q13, 16q, and 14q may be involved in PDGFRA (V561D) tumorigenesis, and that the V561D mutation can occur in the germline state and results in a syndrome that is distinct from neuroendocrine tumors[16]. As the sensitivity of familial GISTs to TKI is similar to that of sporadic GISTs with the same mutation[20], surgical resection and imatinib supplemented with chemotherapy is the best strategy to potentially improve the patient’s prognosis; therefore, we treated our male patient with imatinib 400 mg/day continuously postoperatively until now, and the patient is doing well during follow-up. Due to the small number of case reports and the large number of patients who were lost due to various factors during late follow-up, there is a lack of more solid evidence to support the duration of treatment, and therefore it is controversial whether to extend the duration of imatinib treatment in familial GISTs. However, the fact that no tumor recurrence was seen in our patient in up to 7 years of imatinib treatment could indicate that long-term continuous treatment is at least prognostically beneficial for patients with this mutation type.

STI571 (imatinib) was first used in the clinic in 2002 and achieved significant efficacy in the treatment of a patient with metastatic GI mesenchymal stromal tumor[21], and since then, a new era of imatinib treatment for GISTs has developed. Imatinib has been used as a first-line treatment for KIT/PDGFRA mutant GISTs, but wtGISTs, a mutant subtype, are often resistant to imatinib. Compared with mutant GISTs, wtGISTs show higher chromosomal stability and little genomic imbalance[22], which leads to wtGISTs being less aggressive than the KIT/PDGFRA mutant type, so the proportion of high-risk wtGISTs is low which are usually inert, and patients with wtGISTs generally have better survival, and some studies have found that the median recurrence-free survival (RFS) time in patients with wtGISTs was 7.5 years, and the median OS was 10.1 years[11]. With these in mind, we terminated imatinib treatment in our female patient after 3 years of adjuvant therapy. The good performance of our female patient during long-term follow-up also reinforces the relative inertia of wtGISTs. However, a recent phase III clinical trial found that during a 10-year follow-up period, patients in the 3-year imatinib group had a longer RFS and OS compared to the 1-year group[23]. Moreover, some studies found that regorafenib had therapeutic superiority for wtGISTs, especially in patients with SDHB^IHC- and should be considered as a pre-treatment for advanced wtGISTs[22]. However, due to the limited conditions at the time, we only performed primary genetic testing on the female patient and were unable to perform next-generation sequencing (NGS) to determine more precise typing of wtGISTs as a means of more accurately evaluating the treatment and prognosis of this patient.

As solid tumors require targeted therapy, the process from preoperative computed tomography and gastroscopy to postoperative pathology to confirm the diagnosis, and genetic testing in order to specify the targeted drug has become more mature, but there is still much to learn about familial GISTs. For example, emphasis should be placed on screening for familial GISTs: Patients with GISTs in first-degree relatives; age less than 50 years at diagnosis; localized multifocal GISTs; and those with skin pigmentation changes, mastocytosis, large hands, and other specific symptoms should be highly suspected to have familial GISTs, and germline testing for the KIT and PDGFRA genes should be performed promptly[8]. For familial wtGISTs, NGS should also be performed, to provide patients with matching therapeutic programs and improve their prognosis. For patients with confirmed familial GIST, appropriate targeted drugs should be given according to the results of genetic testing, and regular observation and follow-up should be performed, in order to understand the efficacy of the patient’s treatment and prognosis in a timely manner (Figure 7).

Figure 7 Familial gastrointestinal stromal tumors showing the diagnosis, treatment, and screening process. GIST: Gastrointestinal stromal tumors; wtGISTs: Wild-type gastrointestinal stromal tumors; CT: Computed tomography; NGS: Next-generation sequencing; SDHB: Succinate dehydrogenase complex subunit; IHC: Immunohistochemical staining.

CONCLUSION

Familial GISTs are extremely rare, and the present report provides good strategies and recommendations for the treatment, prognosis, and screening of familial GISTs, with a view to recognizing GISTs as a disease from a different perspective.

ACKNOWLEDGEMENTS

We appreciate the cooperation of the patients and their families during the treatment period.