Malignant portal vein thrombus (PVT) is found in up to 44% of patients with hepatocellular carcinoma (HCC). The nature of the thrombus influences treatment selection. The aim of this study was to assess the safety and efficacy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in determining the nature of PVT in liver cirrhosis and/or HCC.
A prospective study was conducted in 34 patients with liver cirrhosis and/or HCC with PVT. Under EUS guidance, PVT was punctured using a 22 G FNA needle (Cook Medical, Bloomington, IN, USA) followed by monitoring of the puncture tract using color Doppler. Patients were followed for adverse events 2 hours after recovery.
Throughout the 30-month study period, 34 patients, including 24 males with a mean age of 59±8 years, were enrolled. There were 8 patients with known HCC and 26 with no liver masses detected by computed tomography (CT). EUS-FNA from PVT was positive for malignancy in 3 patients (8.8%), of which only 1 patient was diagnosed with HCC by CT and 2 patients were newly diagnosed with HCC after EUS-FNA. No major complications were reported.
EUS-FNA is a safe and effective technique for determining the nature of PVT that does not fulfill the malignant criteria via imaging studies in patients with liver cirrhosis and/or HCC.
Portal vein thrombus (PVT) is increasingly being diagnosed. It has a wide spectrum of clinical presentation ranging from asymptomatic to potentially life-threatening conditions. It is commonly associated with abdominal tumors, liver cirrhosis, and hypercoagulable disorders [
Malignant PVT appears on imaging studies as a low-density plug with contrast enhancement in the arterial phase on both computed tomography (CT) and magnetic resonance imaging (MRI) and may have an arterial signal on Doppler ultrasound (US). However, bland PVT does not enhance with contrast or have any Doppler signal [
Unlike the percutaneous transhepatic approach, endoscopic ultrasound (EUS) offers a unique access and view of the main portal vein up to the porta hepatis. From the first part of the duodenum, the PVT can be punctured with an FNA needle under EUS guidance, avoiding interposing the bile duct, hepatic artery, and collateral circulation. In addition, the EUS-guided approach is supposed to have no false positive results as it eludes unintended inclusion of normal hepatocytes or atypical cells from interposed liver masses occurring with a percutaneous transhepatic approach [
The aim of this study was to assess the feasibility, safety, and efficacy of EUS-FNA in determining the nature of PVT that did not fulfill the malignant criteria via imaging studies in patients with liver cirrhosis and/or HCC.
This was a prospective study conducted in 34 patients with liver cirrhosis and/or HCC with PVT that did not fulfill the malignant criteria by triphasic abdominal CT, over a 30-month study period from May 2017 to December 2019 at the endoscopy unit of Mansoura Specialized Medical Hospital, Mansoura University (Egypt). The study protocol was approved by our ethical committee (Institutional Research Board of Mansoura University, no: 17.06.69), and written consent was obtained from all patients before the procedure.
Patients with liver cirrhosis (with or without hepatic masses) and PVT that did not fulfill the criteria for malignancy by triphasic abdominal CT defined as: neovascularity of thrombus, arterial enhancement with rapid washout, or direct invasion by adjacent hepatic mass [
Patients with PVT fulfilling the malignant criteria by triphasic abdominal CT, patients with extrahepatic metastasis of HCC, patients with decompensated liver cirrhosis (Child-Turcotte-Pugh class C), patients with segmental branch PVT requiring traversing the hepatic parenchyma, patients with a contraindication to interventional endoscopy, such as those with coagulation disorders (International Normalized Ratio ≥1.5, platelet count ≤50.000 cells/mm3), those unfit for sedation (ASA Class 3 or more), and those who refused to be involved in the study.
On the day of the procedure, eligible patients were appointed to the endoscopy room for EUS examination under intravenous propofol sedation. The patient’s medical records were revised for the standard data, which included patient demographics, clinical history, laboratory investigations, major comorbidities that prevent curative management, imaging studies (abdominal US, triphasic abdominal CT, and chest X-ray) with special focus on the nature of PVT and the presence of liver masses. All EUS procedures were performed by two experienced endosonographers using a Pentax linear Echoendoscope EG3870UTK (PENTAX Medical, Tokyo, Japan) connected to a Hitachi Avius ultrasound system (Hitachi Medical Systems, Tokyo, Japan).
Examination of the portal vein was performed from the first part of the duodenum with anticlockwise rotation following the portal vein up to the portal bifurcation at the liver hilum. Examination of the liver was performed from the fundus of the stomach with clockwise and anticlockwise rotation, inspecting most of the liver segments for any focal lesion. From the duodenal bulb, Color Doppler was used to identify the best position to puncture the portal vein, avoiding interposing blood vessels. Under EUS guidance, PVT was punctured using a 22 G FNA needle (Cook Medical, Bloomington). The needle was then moved to and fro 8–10 times while the stylet was slowly removed (slow pull technique). One or two passes were performed to avoid repeated punctures of the portal vein and decrease the risk of bleeding. Subsequently, the portal region was monitored using Color Doppler, and the puncture site was monitored endoscopically to identify any possible bleeding. The specimen was considered adequate using macroscopic on-site evaluation by obtaining a visible core ≥ 4 mm. Tissue material was divided into two parts: the first one was placed in a formalin tube and the second was smeared onto slides and fixed with 95% alcohol instantly labeled and name tagged. No pathologist was present onsite, and all samples were sent to the pathology department for evaluation. After recovery, patients were followed for adverse events for 2 hours and on the next day by phone.
All slides were stained with hematoxylin and eosin, and all tissue samples fixed in formalin were placed in paraffin and stained with hematoxylin and eosin for evaluation of the presence of a histologic core. Immunohistochemical markers were used when needed. All prepared slides and tissue samples were examined by an experienced cytopathologist.
The sample size was calculated using Power Analysis and Sample Size software program (PASS) version 11.0.4. Using the normal distribution curve, for an error of 2% and a level of confidence of 98%, the sample size should be approximately 33 cases. A total of 34 patients were recruited in this study.
IBM’s SPSS statistics (statistical package for the social science) for windows version 25 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis of the collected data. Normally distributed continuous variables were expressed as mean±SD, whereas categorical variables and abnormally distributed continuous variables were expressed as median or number and percentage (as appropriate). As the actual sample size of the malignant PVT diagnosed by histopathology was found to be only 3, the evaluation of
Throughout the 30-month study period, 45 patients were diagnosed with liver cirrhosis (with or without hepatic masses) and PVT that did not fulfill the malignant criteria by triphasic abdominal CT. Of these, 6 patients with coagulation disorders and 1 patient with small PVT in the segmental branch of the left portal vein (requiring traversing the hepatic parenchyma) were excluded. Four patients refused to undergo the procedure. Finally, 34 patients who fulfilled the inclusion criteria, including 24 men and 10 women with a mean age of 59±8 years were enrolled. In 8 patients, liver masses were detected by triphasic CT abdomen with typical features of HCC (enhancement in the arterial phase and rapid washout in the portal and delayed phases); of these, 1 patient was shown to have malignant PVT by EUS-FNA. In 26 patients, no liver masses were detected by triphasic CT abdomen except for 1 patient with 2 small nodules (15 mm) in the right liver lobe with no enhancement in the arterial phase (diagnosed by CT as cirrhotic nodule), which proved to be malignant masses with malignant PVT after EUS-FNA. In the remaining 25 patients, a small focal lesion (10 mm) in the caudate lobe of the liver (not detected by triphasic CT abdomen) was detected by EUS and proved to be a malignant mass with malignant PVT in 1 patient. The other 24 patients were proved to be benign after EUS-FNA, similar to the CT results, as shown in the flowchart (
EUS-FNA from PVT was positive for malignancy in 3 patients (8.8%), of which only 1 patient was diagnosed with HCC by triphasic CT abdomen and 2 patients were newly diagnosed with HCC after EUS-FNA (from cirrhotic nodules in 1 patient and from a small lesion missed by CT in 1 patient). Patients were subdivided after the histopathological results of EUS-FNA into three groups: cirrhosis with benign PVT (24 patients), HCC with benign PVT (7 patients), and HCC with malignant PVT (3 patients). Details of demographic data, laboratory investigations, criteria of the PVT, presence of varices, description of HCC in enrolled patients and different scores used to assess the severity of liver disease and/or stage of HCC are shown in
EUS-FNA was technically feasible in all patients, despite the presence of portal cavernoma or collateral circulation in 16 patients (47%). No major complications occurred in any patient. However, mild abdominal pain was observed in 4 patients (11.76%) and mild self-limited bleeding at the puncture site was observed during endoscopic monitoring in 1 patient (2.94%) (
On review of the 34 aspirates, 3 were positive for malignancy and 31 were negative. Among the 3 positive cases, poorly differentiated adenocarcinoma with positive cytoplasmic reaction for HepPar-1 and Glypican-3 was seen in 1 patient (
A significant impact on the management plan was achieved after EUS-FNA in 4 patients (11.7%). EUS-FNA upstaged 1 patient with HCC from Barcelona Clinic Liver Cancer (BCLC) stage B to stage C and from Hong Kong Liver Cancer (HKLC) stage IIIb to stage IVb, and the patient was treated with sorafenib instead of chemoembolization. In 2 patients, HCC was not diagnosed by triphasic abdominal CT and was diagnosed and staged after EUS-FNA as BCLC stage C and HKLC stage IVa and treated with sorafenib. In 1 patient, portal pyemia was diagnosed after EUS-FNA, which resolved completely on follow-up after treatment with antibiotics.
HCC is one of the most common malignant tumors worldwide and accounts for approximately 90% of primary liver tumors [
Non-invasive imaging studies, such as contrast-enhanced CT or MRI are currently used in the diagnosis of HCC, although they have some limitations. HCC is typically hypervascular on contrast-enhanced CT and shows notable enhancement on arterial phase, with rapid washout on the portal and delayed phases [
Percutaneous transhepatic sampling of a PVT for the diagnosis of HCC was first described by Joly et al. in 1993 [
Despite its well-established efficacy, percutaneous transhepatic US-guided FNA of PVT is not widely utilized, which could be explained by many rationales. First, this technique is associated with complications, such as biliary injury, vascular injury, arteriovenous or vascular-biliary fistula formation, and pseudoaneurysm formation [
EUS-FNA of PVT for the diagnosis of HCC was first described by Lai et al. in 2004 [
In another retrospective study by Gimeno Garcia et al. [
In our study, EUS-FNA upstaged 1 patient with HCC from BCLC stage B to stage C and from HKLC stage IIIb to stage IVb, and the patient was treated with sorafenib instead of chemoembolization. In 2 patients, HCC was not diagnosed by triphasic abdominal CT and was diagnosed and staged after EUS-FNA as BCLC stage C and HKLC stage IVa and treated with sorafenib. To the best of our knowledge, this is the first prospective study evaluating the feasibility and efficacy of EUS-FNA in determining the nature of PVT that did not fulfill the malignant criteria via imaging studies in patients with liver cirrhosis and/or HCC. The main limitation of our study was the relatively small number of enrolled patients. Larger studies are required to confirm our results.
In conclusion, EUS-FNA is a safe and effective technique for determining the nature of PVT that does not fulfill the malignant criteria via imaging studies in patients with liver cirrhosis and/or HCC. The integration of EUS-FNA in the evaluation process of HCC may influence treatment selection. We believe that EUS-FNA should be utilized more frequently in the staging of HCC and in diagnosing the etiology of PVT.
None.
Flowchart of enrolled patients. CT, computed tomography; EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; HCC, hepatocellular carcinoma; HFL, hepatic focal lesion; PVT, portal vein thrombus.
(A) Endoscopic ultrasound examination showing hyperechoic thrombus totally obstructing the main portal vein. (B) Endoscopic ultrasound-guided fine-needle aspiration using 22 G needle for Portal vein thrombus. (C) Multiple small hepatic focal lesions. (D) Cytopathological examination showing sheets of malignant cells with moderate atypia, prominent nucleoli, and occasional mitotic figures, consistent with poorly differentiated adenocarcinoma.
(A. B) Triphasic computed tomography showing non-enhancing portal vein thrombus with no definite liver masses. (C, D) Endoscopic ultrasound examination showing hyperechoic thrombus partially obstructing the main portal branch with no doppler flow inside and multiple periportal veins (cavernoma). (E, F) Endoscopic ultrasound-guided fine-needle aspiration using 22 G needle for both Portal vein thrombus and hepatic focal lesion.
Cytopathological examination showing sheets of malignant cells with moderate nuclear atypia with granular eosinophilic cytoplasm for PVT (A, B), and hepatic focal lesion (C, D), with positive cytoplasmic reaction for HepPar-1 and Glypican-3, consistent with low-grade hepatocellular carcinoma (E, F).
Demographic Data and Laboratory Investigations
Patients subdivisions | Cirrhosis with benign PVT | HCC with benign PVT | HCC with malignant PVT |
---|---|---|---|
Mean (SD) | Mean (SD) | Mean (SD) | |
Age | 58.3 (8.4) | 58.8 (7.5) | 64.67 (2.1) |
Gender | 14 males | 7 males | 3 males |
10 females | |||
Albumin (g/dL) | 3.2 (0.4) | 3.3 (0.2) | 3.2 (0.3) |
Bilirubin (mg/dL) | 2 (2.4) | 0.9 (0.2) | 1.7 (0.6) |
INR | 1.2 (0.1) | 1.2 (0.1) | 1.2 (0.1) |
SGOT (U/L) | 51.2 (44.6) | 39.7 (18.2) | 57.6 (47.9) |
SGPT (U/L) | 31.9 (25.7) | 25.5 (11.1) | 37.6 (18.1) |
WBC (×109/L) | 6.2 (3.4) | 5.5 (3.1) | 2.3 (0.4) |
Hemoglobin (g/dL) | 10.2 (2.1) | 11.5 (2.7) | 9.1 (0.7) |
Platelet (×109/L) | 143.2 (110.2) | 124.1 (61.8) | 63.3 (2.8) |
HCC, hepatocellular carcinoma; INR, international normalization ratio; PVT, portal vein thrombus; SD, standard deviation; SGOT, serum glutamic-oxalacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; WBC, white blood cells.
Criteria of Portal Vein Thrombus and Presence of Varices
Patients subdivisions | Cirrhosis with benign PVT | HCC with benign PVT | HCC with malignant PVT |
---|---|---|---|
Size mean (SD) | 20.1 (4.8) | 17.1 (5.2) | 23.5 (3.9) |
Degree of Occlusion, |
|||
Occlusive | 5 (20.8) | 0 (0) | 0 (0) |
Non-occlusive | 19 (79.2) | 7 (100) | 3 (100) |
Site, |
|||
Only trunk | 14 (58.3) | 3 (42.9) | 0 (0) |
Only branches | 2 (8.3) | 1 (14.3) | 0 (0) |
Trunk & one branch | 4 (16.7) | 3 (42.9) | 2 (66.7) |
Trunk & two branches | 4 (16.7) | 0 (0) | 1 (33.3) |
Extent, |
|||
Splenic vein | 2 (8.3) | 0 (0) | 0 (0) |
Mesenteric vein | 5 (20.8) | 0 (0) | 0 (0) |
Both of them | 4 (16.7) | 1 (14.3) | 0 (0) |
Neither of them | 13 (54.2) | 6 (85.7) | 3 (100) |
Duration, |
|||
Recent | 8 (33.3) | 4 (57.1) | 0 (0) |
Chronic | 16 (66.7) | 3 (42.9) | 3 (100) |
Presence of varices, |
|||
No varices | 6 (25) | 1 (14.3) | 0 (0) |
Esophageal | 14 (58.3) | 5 (71.4) | 3 (100) |
Fundic | 2 (8.3) | 0 (0) | 0 (0) |
Esophageal and fundic varices | 2 (8.3) | 1 (14.3) | 0 (0) |
HCC, hepatocellular carcinoma; PVT, portal vein thrombus; SD, standard deviation.
Description of Hepatocellular Carcinoma in Enrolled Patients
The description of the nature | Previously known as HCC | EUS-FNA of PVT | Number of lesions | Site of lesions | Size of lesions | Previous intervention radiology |
---|---|---|---|---|---|---|
Single nodule | Yes | Benign | 1 | Segment VIII | 1.2 cm | No |
Single nodule | Yes | Benign | 1 | Segment V | 1.5 cm | No |
Binodular | Yes | Benign | 2 | Segment V | 1.8 and 2 cm, respectively | No |
Multinodular | Yes | Benign | 3 | Segments VI (2 lesions), VII (1 lesion) | 3, 4 and 2.6 cm, respectively | TACE |
Multinodular | Yes | Benign | 5 | Segments V (1 lesion), VI (3 lesions), VII (1 lesion) | 1.5, 3.5, 2.6, 1.7 and 1.5 cm, respectively | TACE |
Multinodular | Yes | Benign | 4 | Segments II, V, VI, VII | 4.8, 1.5, 5 and 2.5 cm, respectively | TACE |
Binodular | Yes | Benign | 2 | Segments V, VIII | 5.5 and 2.5 cm respectively | TACE |
Binodular | Yes | Malignant | 2 | Segments V, VIII | 5.3 and 2 cm respectively | No |
Single nodule (Missed lesion by CT) | No | Malignant | 1 | Segment I Caudate lobe | 1 cm | No |
Binodular (Cirrhotic nodules by CT) | No | Malignant | 2 | Segment V | 1.5 cm | No |
CT, computed tomography; EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; HCC, hepatocellular carcinoma; PVT, portal vein thrombus; TACE, trans-arterial chemoembolization
Different Scores Used to Assess Severity of Liver Disease and/or Stage of Hepatocellular Carcinoma
Patients subdivisions | Cirrhosis with benign PVT | HCC with benign PVT | HCC with malignant PVT |
---|---|---|---|
CTP | |||
A | 14 (58.3) | 4 (57.1) | 2 (66.7) |
B | 10 (41.7) | 3 (42.9) | 1 (33.3) |
BCLC staging | |||
Very early stage (0) | __ | 2 (28.6) | 0 (0) |
Early stage (A) | __ | 1 (14.3) | 0 (0) |
Intermediate (B) | __ | 4 (57.1) | 0 (0) |
Advanced (C) | __ | 0 (0) | 3 (100) |
HKLC staging | |||
Stage I | __ | 2 (28.6) | 0 (0) |
Stage IIa | __ | 1 (14.3) | 0 (0) |
Stage IIIb | __ | 4 (57.1) | 0 (0) |
Stage IVa | __ | 0 (0) | 2 (66.6) |
Stage IVb | __ | 0 (0) | 1 (33.3) |
BCLC, Barcelona Clinic Liver Cancer; CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; HKLC, Hong Kong Liver Cancer; PVT, portal vein thrombus.
Procedure Related Complications
Patients subdivisions | Cirrhosis with benign PVT | HCC with benign PVT | HCC with malignant PVT |
---|---|---|---|
Pain | 3 (12.5) | 0 (0) | 1 (33.3) |
Bleeding at puncture site | 1 (4.2) | 0 (0) | 0 (0) |
No complications | 20 (83.3) | 7 (100) | 2 (66.7) |
HCC, hepatocellular carcinoma; PVT, portal vein thrombus.