Prevalence, diagnosis, and treatment of primary hepatic gastrointestinal stromal tumors

Xiao-Hui Qian, Ying-Cai Yan, Bing-Qiang Gao, Wei-Lin Wang

Abstract Gastrointestinal stromal tumors (GIST), which is the most common mesenchymal tumor of the digestive tract, account for 1%-3% of gastrointestinal tumors. Primary stromal tumors outside the gastrointestinal tract are collectively referred to as extra GISTs, and stromal tumors in different regions often have different prognoses. A primary hepatic GIST is a rare tumor with an unknown origin, which may be related to interstitial Cajal-like cells. Although primary hepatic GIST has certain characteristics on imaging, it lacks specific symptoms and signs; thus, the final diagnosis depends on pathological and genetic evidence. This review summarizes all cases of primary hepatic GIST described in the literature and comprehensively analyzes the detailed clinical data of all patients. In terms of treatment, local resection alone or with adjuvant therapy was the prioritized choice to obtain better disease-free survival and longer survival time. For advanced unresectable cases, imatinib mesylate was applied as the first-line chemotherapy agent. Moreover, transcatheter arterial chemoembolization, radiofrequency ablation, and microwave ablation were shown to improve overall survival for selected patients. Liver transplantation was a final treatment option after resistance to chemotherapy developed.

Key Words: Extra gastrointestinal stromal tumor; Treatment; Liver transplant; Review

INTRODUCTION

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumor with an incidence of approximately 1/100000 to 1.6/100000 per year[1-3]. They are a sophisticated mesenchymal tumor, mainly including immature spindle-shaped and/or epithelial-like cell proliferations. Studies have shown that tumorigenesis originates from the interstitial cell of Cajal (ICC) in the gastrointestinal tract, which is the cell responsible for triggering gastrointestinal mobility[4]. The diagnosis of GIST is based on the pathology of the lesion, including cell morphology and immunohistochemistry. According to previous research, CD117 (c-KIT) is expressed in approximately 94%-98% of GIST cases, while CD34 is expressed in 70% of cases[5,6]. GIST occurs in the digestive tract, including the stomach (60%-70%), the small intestine (20%-25%), the colon and rectum (5%), and the esophagus (< 5%)[7].

An extra GIST (EGIST) refers to a type of tumor similar to GIST in tissue morphology and immunophenotype but that originates in the abdominal cavity or retroperitoneum and does not involve the intestinal wall or visceral serosa[8]. Presently, there is no unified understanding of the origin of EGIST due to its low incidence. According to the study by Duet al[9], the incidence of EGIST is < 10% of all GISTs with a definite source. The malignant risk of the tumor, defined as its ability to invade and metastasize, is varied. GISTs are classified into four levels according to their size, mitotic image, and location of the lesion using the National Institutes of Health (NIH) classification guideline, which corresponds to different prognoses and preferred treatment methods. According to previous reports, the risk classification and prognosis of EGISTs are significantly worse than those of gastrointestinal tumors[10,11].

Both GIST and EGIST commonly metastasize to the liver[12-14], but the liver is a rare primary metastatic site of GIST. The majority of studies of primary hepatic GIST (PHGIST) are case reports, and clinical evaluation of different treatment methods has never been established. However, an overall impression of the clinical features, imaging, pathology, and treatment prognosis of PHGIST can be obtained from the limited literature. This review summarizes the etiology, clinical characteristics, diagnosis, and treatment of PHGIST, including cases from the earliest reports found to December 2019. Moreover, this review attempts to clarify the survival and treatment options for this rare disease.

SEARCH FOR CASE REPORTS OF PHGIST PATIENTS

Online databases, including PubMed and China National Knowledge Internet, were used to find relevant studies and further analyze the characteristics of PHGIST without restrictions on publication dates until December 1, 2019. The search terms used were as follows: “extra-gastrointestinal stromal tumors,” “gastrointestinal stromal tumor and liver,” “primary hepatic gastrointestinal stromal tumors,” and “stromal tumors of the liver.” The references for initial studies found were scanned carefully to identify more studies. Eligible documents were selected according to the abstract, and the entire report was subsequently reviewed cautiously. We collected and recorded all reports containing detailed patient information including medical history, laboratory and imaging data, pathological information, treatment records, and prognostic methods (Table 1).

ETIOLOGY OF PHGIST

ICCs are interstitial cells found in the gastrointestinal tract that function as pacemakers for gastrointestinal peristalsis[4]. Current research suggests that GISTs originate from this cell[15]. Moreover, ICC-like cells with a similar structure and function to ICC were observed in organs outside the digestive tract as well as in the vasculature, including the portal vein and mesenteric artery space, using immunohistochemistry in human and animal specimens[16,17]. Rusuet al[18]and Ilieet al[19]demonstrated that ICC-like cells were also present in the human embryonic liver as a single precursor/progenitor cell. Therefore, it is reasonable to speculate that PHGISTs originate from this typical ICClike precursor cell. Some authors also believe that PHGISTs originate from undifferentiated pluripotent mesenchymal stem cells located outside the gastrointestinal tract that then differentiate into ICC[10]. The occurrence of PHGIST on all liver lobes indicates that the distribution of ICC cells in the liver is widespread, and the presence of ICC-like cells in liver tissue may contribute to the development of PHGIST.

The mechanism underlying how ICC develops into a tumor remains largely unknown. Several studies have shown that the function-acquired mutation stem cell factor receptor (KIT) of the receptor tyrosine kinase gene in ICC plays a crucial role in the occurrence of most GIST cases[20]. In previous studies, 65%-80% of GISTs had mutations in theKITgene, and approximately 10% of KIT-negative GISTs had activation mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene[21,22]. In our review, nine patients with gene analysis were included, and the mutation rate was 66% (6/9;n= 4 forKITgene,n= 2 forPDGFRAgene).KITandPDGFRAmutations may also promote the occurrence and development of PHGISTviaactivation and autophosphorylation of downstream signaling pathways.

CLINICAL FEATURES AND LABORATORY TESTS FOR PHGIST

PHGIST patients may have no obvious symptoms with a liver mass accidentally found during routine physical examination or imaging with subsequent confirmatory diagnostic testing. Symptomatic patients show symptoms similar to chronic liver disease, and abdominal pain and a palpable abdominal mass are the most common presentations. Other presenting gastrointestinal symptoms include abdominal discomfort, indigestion, and distension. It is worth noting that two patients presented with significant, acute weight loss in the late stage[23,24]. Some patients may have difficulty breathing because of a large tumor resulting in mechanical obstruction[25,26]. In the later stage of tumor growth, tumor rupture and bleeding can occur, and patients present to the hospital due to sudden onset abdominal pain[27]. Although the incidence is rare, the possibility of GIST should be considered clinically for large spaceoccupying lesions of the liver. PHGIST is currently not associated with any specific tumor marker, except for a few cases that presented with slightly elevated but within normal range alpha-fetoprotein, CA19-9, and CA125 levels[11].

IMAGING AND PATHOLOGICAL DIAGNOSIS

Given that there are no specific radiological features for PHGIST, it is challenging todistinguish PHGIST from other hepatic tumors preoperatively. Thus, these types of tumors are often misdiagnosed. From a morphological point of view, most PHGISTs appear as single round cyst-like solid masses that are occasionally lobulated with bright or fuzzy borders and thick pseudo capsules in some parts with central necrosis and cysts. Tumors may be accompanied by intratumor bleeding, and calcification is rare. It is worth mentioning that magnetic resonance imaging is useful in showing the complex components of tumor tissues[28]. Specifically, diffusion-weighted imaging for solid components shows a significantly high signal, which may be related to malignant tumors[29].

Table 1 Case reports of primary hepatic gastrointestinal stromal tumors

[31]2014 China 56/M No symptom R + L/1 10 Cyst No HR S < 5 CD117 NA No High 12/DFS 12/A[24]2014 India 41/F AP, weight loss R/2 15 Solid + cyst No HR S NA CD117 NA No High 5/DFS 5/A[37]2015 China 60/F No symptom R + C/1 19 Solid + cyst No HR + AT S 10 CD117, DOG-1 NA Yes, KIT exon 11 High 12/DFS 12/A[61]2015 China 65/M AP, appetite reduced L/1 12 Solid + cyst No Chemo S 25 CD117 NA Yes, negative High 13/Met 13/D[36]2015 China 67/F No symptom R/1 7.4 Solid + cyst No HR S + E 8 CD117, CD34 NA Yes, KIT exon 11 High 14/Rec 50/A[62]2015 China 48/F AP L/1 17.6 Solid + cyst No HR NA NA CD117, CD34, DOG-1 NA No High NA NA[45]2016 China 56/F No symptom L/1 2.4 Solid No MWA S 1-2 CD117 60 No High 17/Met 17/A[63]2016 Chile 61/M AP L/1 15 Solid + cyst No HR NA NA CD117, CD34 NA No High NA NA[64]2016 China 61/M No symptom C/1 7.3 Solid + cyst No HR S NA CD117, CD34, DOG-1 2 No High 11/DFS 11/A[32]2016 Japan 70/F No symptom L/1 6.8 Solid + cyst No HR S 35-40 CD117, CD34 NA No High 10/DFS 10/A[65]2016 China 63/M No symptom R/1 13 Solid + cyst No HR S > 5 CD117, CD34 NA No High 60/DFS 60/A[11]2019 China 64/F AP R/1 15 Solid + cyst No HR S > 5 CD117 NA Yes, PDGFRA 12 High 5/DFS 5/A[27]2017 China 50/F Onset AP R/1 15 Solid + cyst Yes HR S 70 CD117, CD34 NA No High 6/Met 6/A[66]2017 China 57/F No symptom L/1 4 Solid + cyst No HR S NA CD117, DOG-1 10 No NA 6/DFS 6/A[43]2017 China 45/F No symptom R + L/> 3 11.5 Solid No TACE + HR S 5 CD117, CD34, DOG-1 3 Yes, negative High 1/Met 18/A[30]2017 Spanish 41/M Abdominal discomfort R + L/1 20 Solid No HR S 5 CD117, DOG-1 10 Yes, KIT exon 11 High 18/DFS 18/A 2018 France 56/M AP R/1 10 Solid No TACE + HR + T + Chemo S 8 CD117, CD34 NA No High 12/Rec 264/D [23]France 59/F AP, weight loss R + L/1 23 Solid + cyst No Chemo S + E 42 CD117, DOG-1 30 Yes, KIT exon 9 High 18/DFS 18/A

[67]2018 China 74/M Abdominal discomfort R/1 5.5 Solid + cyst No HR S < 5 CD117, DOG-1 15 No High NA NA AP: Abdominal pain; AT: Autotransplantation; C: Caudate lobe of liver; Chemo: Chemotherapy; DFS: Disease-free survival; E: Epithelioid; F: Female; HPF: High-power field; HR: Hepatic resection; IH: Immunohistochemistry; L: Left lobe of liver; M: Male (sex), and median lobe of liver (location); Met: Metastasis; MWA: Microwave ablation; NA: Not available; OS: Overall survival; R: Right lobe of liver; Rec: Recurrence; RFA: Radiofrequency ablation; S: Spindle; TACE: Transcatheter arterial chemoembolization; T: Transplantation.

Two types of enhancement imaging patterns for most contrasted scans were seen. First, during the arterial, portal, and delay phases, there was continuous uneven enhancement. If the tumor was a solid mass, it was often difficult to distinguish from hepatic hemangioma[30]. Second, on the fast-forward and fast-reverse phases, the arterial phase was significantly strengthened to a level higher than the normal liver parenchyma. Identification was challenging when equal or low density signals were similar to those for hepatocellular carcinoma, especially when the lesion had a false capsule[11]. In one case, an entirely cystic tumor was seen, which was difficult to distinguish from a hepatic cyst during the early stage. Its size increased during the follow-up course, and PHGIST was finally confirmed[31]. Follow-up imaging studies should be performed, and a diagnosis of PHGIST should be suspected if there is rapid tumor enlargement.

In GIST, positron emission tomography-computed tomography (PET-CT) is considered to be the most sensitive method for diagnosis as well as for evaluating the efficacy of molecularly targeted drugs. Because PET-CT has essential value in diagnosis and staging, prediction of malignant potential, treatment decision, efficacy assessment, and follow-up monitoring, it has been clinically recognized and included in the 2010 National Comprehensive Cancer Network Guide Guidelines Medium[6]. In the literature, PET-CT was used to exclude liver GIST from extrahepatic lesions with a maximum standardized uptake value of 6.30-6.85[28,32]. Importantly, even if patients have a characteristic image without a history of hepatitis and alpha-fetoprotein levels are not elevated, the possibility of PHGIST should be considered in the differential diagnosis. However, the final diagnosis should still be based on pathology and immunohistochemistry.

EGISTs have the same morphology, immunohistochemistry, and molecular characteristics as conventional GISTs, including metastatic GISTs. The histopathological diagnostic criteria for GISTs have been firmly established. Histologically, there are three main PHGIST types. The spindle cell type predominates, while epithelioid cell and mixed cell types account for only a small portion of cases (11.4%, 4/35). The tumor cells of most patients who underwent immunohistochemistry expressed CD117 and CD34, which showed a positive envelope and/or diffuse cytoplasm. Only one case of GIST was found not to express CD117, but it was CD34 positive[33]. The diagnosis of GIST cannot be ruled out in a patient with a tumor morphologically consistent with GIST but without CD117 expression. In this case, further detection of mutations in thec-KITandPDGFRA-αgenes is required for diagnosis. Moreover, GISTs can also express DOG1, especially in cases with aPDGFR-αgene mutation without ac-KITmutation with an overall sensitivity similar to that of CD117[34]. The combination of DOG1 and CD117 expression for the diagnosis of GIST has functional complementarity[35].

We believe that a precise diagnosis requires immunohistochemistry and molecular examination, which may exclude other rare types of hepatic mesenchymal epithelioid tumors, such as epithelioid vascular leiomyomata, leiomyosarcoma, and malignant melanin tumors. It should be emphasized that the liver is the most likely place for GIST metastasis and that primary GIST of the liver is rare. Therefore, to ensure an accurate diagnosis, it is necessary to exclude tumors in other common locations of the gastrointestinal tract by using methods such as barium radiography, digestive endoscopy, and PET-CT. In addition, CT or ultrasound-guided fine-needle aspiration biopsy is commonly used to diagnose unresectable hepatic tumors[23,36]. Puncture biopsy can also be used to definitively diagnose patients with inoperable PHGIST.

OVERALL CONDITION OF THE CASE REPORTS

There were 34 reports of PHGIST in the literature, with a total of 35 cases as follows: twenty-three in China, one in South Korea, two in France, two in India, three in Japan, and four in other countries (Table 1). Patients ranged in age from 17-79 years with an average age of 56 years. Seventeen cases were male, seventeen cases were female, and one case had no reported gender. Of all cases, 26.6% (15/35) were asymptomatic and found on routine physical examination. The presenting symptom was abdominal pain of varying intensity in 11 patients. One case presented with acute rupture due to tumor rupture, and the other presenting manifestations included loss of appetite (n= 2), indigestion (n= 1), abdominal discomfort (n= 2), weight loss (n= 2), and shortness of breath (n= 2). Tumors were located in all lobes of the liver with the majority being in the right lobe (n= 22). Most patients presented with a single hepatic mass (n= 30); however, two patients had more than two masses. The tumors ranged in diameter from 2.3 cm to 44.0 cm (median, 15.0 cm; mean, 13.8 cm). On imaging, there were three, eight, and twenty-four cases of cystic masses, solid masses, and mixed masses, respectively.

Of the thirty-five patients, twenty-five underwent local hepatectomy alone or in combination with adjuvant therapy, two underwent transcatheter arterial chemoembolization (TACE), and two underwent liver transplantation. Three patients received different interventions for various reasons: One patient (tumor size 5.1 cm) underwent radiofrequency ablation, one patient (tumor size 2.4 cm) was treated with microwave ablation, and one patient with large cystic masses (largest tumor > 20 cm) underwent repeated cystic drainage. The remaining five cases were not treated surgically, including one patient who was discharged without any treatment. Followup data were obtained from 24 patients, and recurrence usually occurred within 1 year of the operation. The metastatic sites included the liver, lymph nodes, bones, and brain. Most patients were categorized as high risk according to the risk stratification criteria of the 2008 version of the NIH guidelines, and 16 patients received adjuvant therapy or chemotherapy alone. Nineteen of twenty-five patients (76.0%) had a mitotic index ≥ 5/50 high-power fields.

Ki-67 expression was detected in ten patients, and eight patients had a ratio more than 5%. Among thirty liver GIST specimens, spindle cell morphology was observed in twenty-five (83.3%), epithelioid cell morphology was observed in one (3.3%), and mixed cell morphology was observed in four (13.3%). Of the 35 (97.1%) specimens, 34 were positive for CD117, and 18 (51.4%) were positive for CD3. Five of six cases (83.3%) were positive for DOG-1. Genomic mutations were examined in four specimens.KITmutations in exon 11 were found in three of nine specimens,KITmutations in exon 9 were found in one specimen,PDGFE 12mutations were found in two specimens, and the remaining three specimens had no apparent genetic mutations. The 2008 version of NIH risk classified thirty-three patients as high risk (94%), and the other two patients could not be classified because of incomplete data. Seventeen studies reported prognostic results. During follow-up, five patients were diagnosed with recurrent or metastatic tumors. Metastases were found in the following organs: hilar and pulmonary lymph nodes (n= 1), stomach (n= 1), lungs (n= 1), brain (n= 1), and bone (n= 1). Two patients who did not undergo surgery died of primary liver EGIST at 13 mo.

PHGIST TREATMENT

As there are few cases of PHGIST, the main treatment methods follow the treatment protocol of GIST, which reflects the concept of comprehensive therapy as a whole. Based on a review of all cases, we believe that lesion resection with or without combined chemotherapy is the best choice. Of the 30 patients with PHGIST who received local hepatectomy alone or in combination with chemotherapy, 23 (76.7%) patients had a survival > 6 mo. For locally advanced tumors, after an evaluation is performed, obtaining R0 resection should be attempted followed by adjuvant treatment. In one case, a liver mass was located in the right posterior lobe of the liver, which spread to the right adrenal gland[11]. Because conventional methods could not be used for resection, external hepatectomy and autotransplantation were performed[37]. Interestingly, the majority of reported cases of PHGIST were detected at a resectable stage with < 15% of patients not being treated with surgery.

According to the recommendations of the NIH, almost all PHGISTs are high risk and thus require adjuvant treatment. Among chemotherapeutic agents, imatinib is recommended as a first-line treatment[38,39], although less common drugs such as sunitinib and regorafenib are sometimes used[40,41]. GIST is caused byc-KITorPDGFRmutations in precursor cells, leading to the continuous activation of tyrosine kinase and uncontrolled cell proliferation and differentiation. Therefore, the use of imatinib, a tyrosine kinase inhibitor, has completely changed the concept of surgical treatment and comprehensive treatment of GIST[38]. For PHGIST, almost half of the patients studied received imatinib as a basic or adjuvant treatment with satisfactory results. Although no patient received imatinib as a preoperative adjuvant treatment, we believe that after the evaluation of certain advanced tumors, it can be used as neoadjuvant therapy to minimize the lesion and obtain possible R0 resection.

Imatinib is also the first-line therapy recommended for patients with unresectable tumors or who have obvious contraindications to surgery. A needle biopsy is required to confirm the diagnosis for nonsurgical treatment; however, it is necessary to ensure that the biopsy is performed well. It is worth noting that in patients treated with imatinib, even if the lesion does not shrink significantly during follow-up, this may indicate stable cancer with a prolonged survival time. Joyonet al[23]reported a patient who had only minimal response at 6 mo follow-up (< 10% reduction in diameter), but who survived 18 mo following diagnosis. For patients who can undergo resection after relapse, the tumor should be resected, and imatinib should be added or continued. In GIST cases, the 2 years of progression-free survival for patients treated with imatinib was 77%, which may be similar for PHGIST[36,42,43]. Conventional chemotherapeutics such as doxorubicin combined with cisplatin were seldom used in PHGIST cases; however, they may contribute to the maintenance of tumor stability. In one report[36], systemic chemotherapy consisting of 50 mg/m2doxorubicin and 50 mg/m2cisplatin every 3 wk resulted in improved symptoms with reductions in dull upper abdominal pain and tumor size on palpation after the first treatment cycle.

PHGIST may be asymptomatic early, but the tumors grow quickly, and rupture and bleeding may occur. Indeed, several cases of intratumor bleeding have been reported. Transarterial embolization can be performed to stanch bleeding. Other treatment strategies are used in specific clinical situations. In two patients with small tumors, local treatment was attempted with radiofrequency[44]and microwave[45]ablation resulting in a satisfying prognosis. TACE is a palliative treatment for patients with unresectable primary hepatic angiosarcoma. Liaoet al[43]reported a case who accepted TACE to slow tumor progression and reduce lesions, ultimately achieving R0 resection of the tumor.

Resistance to chemotherapy treatment may eventually occur with the prolongation of imatinib treatment time. For GIST, it has been reported that 15% of patients are primarily resistant to the drug[46], In general, 88% of patients suffer from recurrence about 2 years after imatinib treatment due to the secondary resistance mutations in additionalKITexons[47,48]. Given the poor results of palliative treatment including chemotherapy, ablation, and TACE in patients with tyrosine kinase inhibitor drug resistance, liver transplantation may be the only treatment that may improve prognosis and prolong the overall survival time[49]. In a case reported by Joyonet al[23], a patient received a first course of lipiodol chemoembolization, but a second intrahepatic lesion was discovered in the left lobe 3 mo later. After evaluating the transplantation indications, liver transplantation was proposed. The patient eventually died 22 years after the initial diagnosis, 21 years after liver transplantation, and 9 years after tumor recurrence. According to the study by Frillinget al[50], adjuvant treatment with imatinib initially given before transplantation for a period > 2 years may yield better results. Maoet al[37]performed extracorporeal hepatic resection and autotransplantation for PHGIST. The patient then received imatinib adjuvant therapy and had no evidence of recurrence on CT or ultrasound after 12 mo.

LIMITATIONS OF THE ANALYSIS

Our study is a retrospective analysis based on previous literature, and it inevitably has some limitations. First, the sample size was relatively small. Only Chinese and English language literature was searched, which may have led to uneven regional sampling. Second, this review included case reports from East and South Asia, North and South America, and western and southern Europe; therefore, the demographic heterogeneity across different studies is inevitable. Third, combined case report analyses are somewhat limited and inaccurate due to the difference in the quality of care between hospitals and institutions. We tried to minimize the analysis of data from case reports and preferred to focus on the essential characteristics of the patients in these reports.

CONCLUSION

PHGISTs are sporadic. It remains challenging to accurately determine the liver as the primary site of GISTs to obtain an accurate diagnosis. The first-line treatment of PHGIST is surgical intervention. Additionally, imatinib can be used as adjuvant therapy for locally advanced tumors and as the first-line treatment for unresectable tumors, recurrence, and metastases. Overall, existing studies have shown that PHGISTs are high-risk tumors compared with common GISTs, meaning that the prognosis of PHGIST is worse than that of gastric and small intestine GIST. Therefore, involvement of a multidisciplinary team is needed for the diagnosis and treatment of patients with PHGIST.