Patient Characteristics
In total 53 articles were collected [1-53], including 5 (9.4%) retrospective studies [3, 11, 23, 50, 53], 4 (7.5%) case series [1, 21, 43, 49], and 44 (83.0%) case reports [2, 4–10, 12–20, 22, 24–42, 44–48, 51, 52], with 187 patients involved.
Patients were at the age of 58.7±12.4 (range, 23-84; median, 60) years (n=93). Gender was known for 105 patients: 88 (83.8%) were male and 17 (16.2%) were female (χ2=96.0, p<0.001). In total 166 (88.8%) patients had a medical history of liver disease (Table II).
Patients were devided into 6 groups according to treatment of choices: TACE, surgery, radiotherapy, chemotherapy, intervention and supportive care. Besides, some patients were not treated, while treatment was not described in others.
In 8 patients with recurrent HCC, previous treatment was hepatectomy in 2 (25%) patients [1, 30], TACE in 3 (37.5%) patients [1, 19], and TACE plus direct-acting antiviral therapy (sofosbuvir) [5], radiofrequency ablation plus doxorubicin and sorafenib chemotherapy [15], and TACE plus radiofrequency ablation plus sorafenib [40] in 1 (12.5%) patient each.
The clinical symptoms were described for 36 patients, with pedal edema being the most common (Table I). Blood test results on admission were shown in Table III.
The timing of diagnosis of RA thrombi was described for 53 patients: at HCC recurrence in 5 (9.4%) patients [1, 5, 13, 15, 30], at HCC progression in 13 (24.5%) patients [1, 17, 19, 34, 36–38, 40, 42, 48, 51], and at the first HCC diagnosis in 35 (66.0%) patients [2, 4, 6–10, 12, 14, 16, 18, 20–22, 24–29, 31–33, 35, 39, 41, 44–47, 49, 52].
The time interval between diagnoses of HCC and of RA tumor thrombus was 33.5±22.1 (range, 9–56; median, 35) months (n=4) for patients with recurrent HCC and 33.4±46.2 (range, 2–144; median, 12) months (n=9) for patients at HCC progression (t=0.002, p=0.998).
Tumor Characteristics
The size of liver tumor was described for 57 patients. The calculated tumor size was 8.4±4.1 (range, 1.3–21; median, 7.6) cm, with only 3 (5.3%) tumors of 3 patients <3 cm [1, 6, 51].
The location of liver tumors were described for 56 patients: 16 (28.6%) were located in the left lobe [2, 8, 12, 16–18, 21, 27, 31, 35, 46, 47, 52, 53], one of which extended to the right lobe at a later stage [17], while 35 (62.5%) tumors were located in the right lobe [1, 6, 7, 9, 10, 13, 14, 20–22, 24, 28, 29, 34, 39, 41, 42, 48, 49, 53], and 5 (8.9%) involved both lobes [25, 26, 32, 33, 53] (χ2=37.0, p<0.001). There was no significant difference in tumor size between tumors located in the left and in the right lobes (8.6±4.2 cm vs. 8.9±4.4 cm, t=-0.207, p=0.837).
The segmental locations of liver tumors were described for 31 patients, and a total of 68 segments were invaded with 1–4 invaded segments in each patient [2, 10, 13, 18, 21, 22, 25, 27–29, 34, 41, 42, 53]. Segments 7 and 8 were the most commonly invaded by liver tumors (Figure 1).
Apart from RA thrombus, tumor thrombus in the alternative vasculature developed in 106 (56.7%) patients, and IVC thrombus was the most common (Table IV). The maximal size of RA tumor thrombus was 4.6±2.3 (range, 2–15; median, 4.4) cm (n=42). RA tumor thrombus-induced tricuspid orifice occlusion of different degrees was noted in 3 patients [10, 15, 31].
Simultaneous lung metastasis was found in 6 patients [2, 8, 10, 17, 37, 47]. Diaphragm metastasis occurred in 1 patient [7].
Treatment
Liver tumor was resected while RA tumor thrombi was not resected but treated with subsequent chemotherapy with bevacizumab in 1 patient [48], and RA and IVC tumor thrombi were removed while liver tumor was not resected but treated by microwave ablation/TACE in 2 patients [26, 16]. Their survival time was 6, 6 and 7 months, respectively (median, 6 months).
The 30 patients with a one-stage operation for both HCC and RA thrombus survived 14.4±12.8 (range, 1.3–56; median, 11.2) months (n=25) [2–4, 12, 13, 18, 20, 21, 25, 28–30, 35, 42, 43, 45, 49–52]. One patient receiving a two-stage operation survived 6 months [38]. The surgical operation was performed under cardiopulmonary bypass (CPB) in 18 patients [2, 3, 18, 21, 28–30, 35, 38, 43, 45, 51, 52], under veno-venous bypass in 1 patient [25] and with total hepatic vascular exclusion (THVE) with no CPB in 15 patients [3, 4, 12, 13, 20, 42, 49, 50].
The operation time was 9.1±2.5 (range, 5.6–12.3; median 9.0) hours (n=12) [4, 7, 12, 25, 29–31, 35, 42, 45, 51, 52], the CPB time was 40.6±23.9 (range, 16–100; median, 38) min (n=9) [2, 7, 12, 29, 30, 45, 50, 51, 52], and the hepatic occlusion time was 29.4±26.3 (range, 10-87; median, 19) min (n=11) [4, 12, 13, 20, 25, 29–31, 42, 45, 52]. The total blood loss amount was 3.562,0±2,692.2 (range, 650-8,200; median, 2,692) mL (n=10) [7, 13, 25, 29–31, 35, 42, 51, 52].
TACE, solely or combined with chemotherapy/radiotherapy/surgery, was done 1–7 times per patient, and thalidomide 100 mg bid was the usual regimen. Complete/partial regression of liver and RA tumor, α-fetoprotein decrease and symptom-free were observed at 1–4 months [1]. Selective embolization with pirarubicin 30 mg, oxaliplatin 200 mg, hydroxycamptothecine 20 mg and iodized-oil was also reported obtaining similar effects to thalidomide [46].
Systemic chemotherapy with sorafenib were applied in 4 patients [9, 14, 27, 47].
Two patients received interventional treatment: mechanical thrombectomy of the right atrial mass with subcutaneous enoxaparin and oral sorafenib in one patient who did not respond to sorafenib and died [41], and percutaneous microwave ablation in another patient in whom intrahepatic tumor recurrence occurred 3 months later and patient was alive as the tumor was completely ablated by TACE and salvage microwave ablation [22].
Radiotherapy included external beam radiotherapy with 2500 cGy in 5 fractions in one patient, the RA mass was reduced at 1 month but died of multiple metastasis [15] and hypofractionated radiotherapy in 18 patients with 2 alive at a follow-up of 3–40 month [23]. The outcomes of each group were shown in Table V.
Follow-up and Survival data
Patients had a follow-up of 15.7±16.6 (range, 0.5–97; median 10) months (n=75). The patients receiving radiotherapy had the longest follow-up among all groups (Table VI). Intra- and/or extrahepatic recurrence of HCC was the major mobidity (Table VII).
The overall survival rate of this cohort was 40.8% (20/49). The survival rate of patients receiving TACE was 33.3% (4/12) and that of surgical patients was 41.9% (13/31) (χ2=0.3, p=0.735). The prognosis of the patients with different treatments was shown in Table V. The survival time of TACE patients was longer than that of surgical patients, but lack of a statistical significance (20.0±3.4 months vs. 13.3±12.1 months, t=-1.455, p=0.151). The mortality rates in a decremental sequence for patients receiving different treatments were supportive care > radiotherapy > surgery > TACE > interventional treatment (Table VI). No difference was found in mortality between patients reported from case reports and those from non-case reports (Table VIII).
The pathology of HCC was available for 18 patients: 10 (55.6%) were moderately differentiated [2, 11, 13, 25, 35, 42, 52], 3 (16.7%) were moderately to poorly differentiated [7, 18, 33], and 5 (27.8%) were poorly differentiated [4, 11, 12, 29, 30].