As primary hepatic GISTs that occur outside the gastrointestinal tract are extremely rare, there was only one case in our database, which includes a total of 632 cases of GISTs from 2006 to 2019 (14 years). Most literature consists of case reports, or metastatic hepatic GISTs, with limited data. Compared to previous study (22 cases), the current study represents the largest number of hepatic GISTs consisting of 37 cases, and even evaluated the relationship between tumor density and clinicopathological features.45 It implied that mitotic index exceeding 5/50 HPF or tumor size exceeding 5 cm was the important point to distinguish primary hepatic GISTs from gastric GISTs in DFS and DSS, which previous research had never reported. The result was also in accordance with the conclusion of modified NIH risk classification that gastric and non-gastric GISTs with tumor size less than 5 cm or mitotic indices less than 5/50 HPF shared the same risk classification (very low or low risk), however, for those with greater tumor sizes or higher mitotic index, non-gastric GISTs showed higher risk classification than gastric GISTs.
Recently, the ICC or ICC-like cells have been reported to exist in organs outside the gastrointestinal tract. Miettinen et al. described a primitive ancestor cell, present inside and outside of the intestines can give rise to GISTs and GIST-like extra-intestinal tumors, or that CD117 positive phenotype can be expressed in cells at inside and outside of the intestines.46 Popescu et al. demonstrated that ICC-like cells occurred in human exocrine pancreas.47 Ahmadia et al. confirmed that the Cajal cells were present in the extrahepatic bile ducts.48 Fu et al. identified ICC-like cells in the liver.49 Together, these studies imply the possibility of primary hepatic GISTs. Lack of specific clinical manifestations, the main symptoms were abdominal pain, discomfort, abdominal lesion, and abdominal distension. We report the positive expression of CD117 and CD34 was 97.1% and 66.7% in hepatic GISTs, which were in accordance with the results of previous studies about gastric GISTs (CD117, 95%; CD34, 70%).50 The lesion distribution of hepatic GISTs included left lobe, right lobe and caudate lobe.
In the study, 25 cases (69.4%) showed mixed lesion and 4 cases (11.2%) showed cystic lesion. Mixed or cystic lesions of the liver are likely to be hepatic carcinoma, metastatic hepatic tumors, hepatic cyst, hepatic hemangioma, liver abscess, hepatic mucous cyst. The CT images of primary hepatic GISTs were similar to those of metastatic hepatic GISTs, presenting with heterogeneous hypodense lesions due to necrosis, hemorrhage and cystic degeneration of the mass. The CT image of our patient with heterogeneous hypodense mass was shown in Fig. 4. Majority studies demonstrated hepatic GISTs showed peripheral enhancement in the arterial phase and progressive concentric enhancement in the portal venous phase.45 Our report of primary hepatic GIST was consistent with previous study with progressive concentric enhancement in CT images. However, Hyum reported a case of primary hepatic GISTs showed the same degree of enhancement compared to live parenchyma in the arterial phase and persistent enhancement in the portal venous and delayed phase.32 And he deemed GISTs were consisted of a wide range of pathologic spectrum, contributing to the discrepancy of different enhancement degree and pattern.
The present study even took consideration of the relationship between tumor density (solid, cystic and mixed lesion) and clinicopathological features, and discovered larger tumors were likely to display mixed density and tumors with mixed lesion were associated with high risk classification. Tumor density may be an indicator of risk classification for primary hepatic GIST. Size, mitotic count, anatomical location and rupture are important factors in evaluating the prognosis.51 Larger tumors were likely to display mixed density, perhaps due to insufficient blood supply, leading to tumor necrosis or cystic degeneration. Tumors with mixed lesion were associated with high risk classification because of the connection between larger size and risk classification.
The radiological features of heterogenous hypodense and hypervascular nature of the tumor indicated hepatic GISTs, but also suggested other diagnoses, such as hepatocellular carcinoma. GISTs was definitively diagnosed by the histopathological examination of a tissue sample. The different cell morphology (spindle, epithelioid or mixed), distinctive immunohistochemical detection of CD117, CD34 and Dog-1 and molecular alterations features of c-KIT and PDGFEA genes mainly formed the diagnosis criteria of GIST. Li et al. demonstrated that (EUE-FNA) was the quickest and least painful way to obtain an accurate tissue diagnosis of hepatic GISTs.44 However, because of the small amount of obtained tissue, diagnosing gene mutations status is difficult by this method and bleeding or implantation metastasis is possible. Most cases involving the study were diagnosis of primary hepatic GIST, by postoperative histopathological examination and few cases without operation were diagnosed by fine needle aspiration cytology.
Bleeding, bloating, abdominal discomfort, organ dysfunction and distant metastasis resulting in multiple organ failure were the main reasons for patients to seek for medical care. Compared with gastric GISTs, bleeding was less common in hepatic GISTs (P < 0.001) as well as spindle morphology (P < 0.001). Primary hepatic GISTs were most frequently newly diagnosed as higher risk than gastric GISTs (91.8% vs 34.8%, P < 0.001). Surgery was considered to be first-line therapy for resectable GISTs. R0 resections significantly improved survival of patients with primary hepatic GISTs and reduced postoperative recurrence rate.52 It was reported extracorporeal hepatic resection and auto-transplantation (ECHRA) is an alternative method for tumors with large size, lesion extension or location adjacent to critical structures.53–54 In our study, 25 patients had received R0 resection, and 5-years DFS and DSS rate were 19.4% and 53.7% in patients with follow-up data (19 patients), including one who underwent ECHRA and survived for 22 years, the longest disease-specific survival as far reported. ECHRA is likely to be a promising therapeutic strategy for large or awkwardly located hepatic GISTs with no metastasis. Radiofrequency ablation was performed in 2 cases with very low risk classification, one case with 17 months of disease-free time. Otherwise, imatinib, a tyrosine kinase inhibitor against c-KIT and PDGRA, was widely used to treat unresectable GISTs, post-surgical relapses or metastases after surgery, or postoperative adjuvant therapy, which had been shown to improve survival of GISTs.55 Efficacy of target therapy was associated with mutation status. Though wild type GISTs patients were treated with imatinib with a worse response, imatinib was also considered to improve the overall disease control rate (> 60%).56–58 Sunitinib was recommended as a second-line treatment for recurrent, metastatic or unresectable GISTs and the first choice for generalized progression after standard-dose imatinib therapy. As non-gastric GISTs have higher risk of recurrence than gastric GISTs, 3 years of adjuvant therapy was recommended for patients suffered from hepatic GISTs with intermediate risk classification. The current study showed patients with intermediate or high risk classification received imatinib or sunitinib therapy only in 14 out of 25cases. Two patients received sunitinib therapy due to generalized progression under the standard dose and survived for 8 months and 53 months, respectively.
According to the NIH risk classification, gastric and non-gastric GISTs with tumor size less than 5 cm or mitotic index less than 5/50 HPF shared the same risk classifications (very low or low risk). However, for those with larger tumor sizes or mitotic index, non-gastric GISTs are higher risk than gastric GISTs. Our analysis of survival data associated with tumor size and mitotic index implied that with tumor size exceeding 5 cm or mitotic index exceeding 5/50 HPF, DFS and DSS were worse in patients with hepatic GISTs. The study implied than mitotic index exceeding 5/50 HPF or tumor size exceeding 5 cm may be the important factors to distinguish hepatic GISTs from gastric GISTs in DFS and DSS. Dematteo et al. found that tumor size, mitotic rate and location independently predicted recurrence after resection of primary stromal tumors.59 And previous studies ever reported they were important malignant potential predictors of GIST.60 Our multivariate analysis of prognostic factors of hepatic and gastric GISTs showed location and NIH risk classification to be independent prognostic factors for DFS and location and size were significantly associated with DSS. Compared with gastric GISTs, hepatic GISTs suffered from worse 5-year DFS rate (19.4% vs 80.9%, P < 0.001) and DSS rate (53.7% vs 92.9%, P < 0.05).
Our study has some limitations, mainly for its retrospective design and incomplete data collection. Firstly, the small hepatic GISTs sample size may have produced selection bias, leading to possible false-positive or -negative results. Secondly, we didn’t make comparisons of survival data by tumor size less than 5 cm and mitotic index less than 5/50 HPF for limited data acquisition. Finally, we also did not perform subgroup analyzes of clinicopathological features and prognosis between hepatic and gastric GISTs, or between primary hepatic GISTs and other EGISTs, such as pancreas or omentum. Optimal treatment for hepatic GISTs should therefore be further studied.