DOI:
Original papers
Accuracy of endoscopic ultrasound-guided biopsy of focal liver lesions
Vlad Andrei Ichim
1, Romeo Ioan Chira
1,2, Petru Adrian Mircea
1, Georgiana Anca Nagy
1,2, Doinita Crisan
3, Mihai Adrian Socaciu
411st Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 2Emergency County Hospital Cluj, 1st Medical Clinic, Gastroenterology Department, 3Emergency County Hospital Cluj, Department of Pathology, ”Iuliu Haţieganu” University of Medicine and Pharmacy, 4”Octavian Fodor” Regional Institute of Gastro- enterology and Hepatology, Department of Radiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Received 25.09.2019 Accepted 27.12.2019 Med Ultrason
2020, Vol. 22, No 1, 20-25
Corresponding author: Romeo I. Chira, MD, PhD
1st Medical Clinic, Gastroenterology Department 3-5 Clinicilor street,
400006, Cluj Napoca, Romania Phone: +40 751 130 280 E-mail: [email protected]
Introduction
Endoscopic ultrasonography (EUS) has become an indispensable diagnostic method in gastroenterology and
new indications for EUS continue to emerge [1]. There has been a sustained progress in EUS diagnostic, poten- tial due to constantly improving imaging systems and needles, which resulted in better tissue acquisition and lower technical failure rate [2-7].
Ultrasonography (US) or computed tomography (CT) guided liver biopsy are frequently used for the diagnosis of focal liver lesions. Although both methods have a high diagnostic accuracy of approximately 90% [8-13], in cer- tain patients, US or CT guidance may be impossible be- cause of suboptimal visualization of small liver lesions or the lesions are difficult to be differentiated from the normal parenchyma.
Abstract
Aim: Endoscopic ultrasound (EUS) has become an indispensable method for diagnosis in gastroenterology and new indications for EUS continue to emerge. However, there are limited data regarding the accuracy of EUS-guided biopsy of hepatic focal lesions. The aim of this study was to assess the diagnostic yield of EUS-guided fine needle aspiration (FNA) of focal liver lesions. Material and methods: We conducted a prospective study in which patients with focal liver lesions, detected by transabdominal ultrasound and computed tomography or magnetic resonance imaging, underwent EUS-guided FNA to determine the diagnostic yield of the procedure. Results: In 47/48 of patients, the results of EUS-FNA were positive for malignancy, while in one case the acquired fragment was insufficient for appropriate histological analysis. Diagnostic yield was 0.98. In 83% of the cases biopsies were taken from the left lobe and in 17% from the right lobe with the same technical success rate. The most common diagnosis was metastatic adenocarcinoma of the pancreas (26% cases) followed by cholangio- carcinoma (17% cases). Concurrent sampling of other sites in addition to the liver and/or primary tumor was realized in 35%
of the cases, with results that correlated with the liver biopsy and with the primary tumor biopsy. We reported no immediate or long-term complications in any of the patients. Conclusions: EUS guided fine needle aspiration/biopsy of focal liver le- sions is safe, provides a very high diagnostic accuracy and should not be considered only as a rescue method after failure of percutaneous guided biopsies.
Keywords: endoscopic ultrasound-fine needle aspiration (EUS-FNA); liver biopsy; focal liver lesions DOI: 10.11152/mu-2078
The usefulness of EUS guided fine needle aspiration (EUS-FNA) of focal liver lesions has also been investi- gated, and it has a similar diagnostic yield, ranging from 80-100% [14]. However, EUS has several advantages over other imaging modalities regarding optimal visuali- zation of the liver, availability without regard to patient body type, presence of massive ascites, lesions in the caudate lobe or non-cooperating patients. These advan- tages combined with limited adverse events, makes EUS an excellent modality for diagnosis and staging of ma- lignant conditions concerning the liver. Still, there are a limited number of papers that analyze the feasibility and safety of EUS guided FNA for focal liver lesions. EUS and FNA of liver lesions is considered a “rescue” diagno- sis method, after an unsuccessful or impossible approach by classical biopsy guiding methods [14-16].
The objective of this study was to assess the diag- nostic yield and safety of EUS-guided fine needle aspira- tion FNA of focal liver lesions and to discuss situations when to choose this procedure over the US/CT guided biopsy.
Material and method Patients
We performed EUS-FNA for the following indica- tions: to assess primary lesions and establish tissue di- agnosis from the liver masses identified by US/CT/MRI, for pancreatic tumors with focal liver lesions, and in cas- es where due to poor accessibility it was difficult to ob- tain a tissue sample through percutaneous biopsy. In this prospective study, we evaluated 48 consecutive patients (21 females, average age of 66.3 years old, range 40-83 years old) who underwent EUS-FNA for the diagnosis of liver lesions in our institution, between August 2017 and March 2019. In all, but 2 cases, the primary tumor
had been identified via imaging or endoscopy. The in- clusion criteria were age over 18 years old, presence of solid liver masses revealed by US/CT/MRI that required biopsy (fig 1a). The exclusion criteria were hemostasis and bleeding disorders (international normalized ratio
>1.5 [normal range 0.85–1.25] or platelet count <80 000/
mm3 [normal range 150 000–450 000/mm3]) and poor accessibility to the tumor by EUS. Written informed consent was obtained from all patients before the pro- cedure. This study was approved by the local Ethics Committee.
Endoscopic ultrasound-guided fine-needle biopsy procedure
EUS-FNA was performed by a single expert endo- sonographer using a linear array echoendoscope (Olym- pus GF-UCT180 with ultrasound processor EU-ME 2).
Tissue acquisition was performed with a 22G needle (Expect®, Boston Scientific or EZ Shot 3+®, Olympus Medical Systems).
Following the evaluation of the target lesion, includ- ing real-time Doppler US (fig 1b), FNA was performed either trans gastric for the left lobe (fig 1c) or transduo- denal for the right lobe. The needle was advanced into the target lesion under EUS guidance. Once the lesion was punctured, the stylet was detached. The specimen was obtained by moving the needle back and forth within the lesion while applying negative pressure with a 10 mL syringe. Suction was released by closing the syringe lock and the needle was removed afterwards. Aspirated speci- mens were displaced by reinserting the stylet. The tissue sample was carefully inspected after each pass to deter- mine the successful acquisition of specimen, with addi- tional passes performed if necessary. The aspirate was then immersed in formalin for histology (fig 1d) and in some cases, when we procured a small amount of tissue laid out onto glass slides for cytology smears.
Fig 1. a) Axial contrast-enhanced computed tomography – liver metastasis of a neuroendocrine tumor; b) Endoscopic ultrasound (EUS) with color Doppler mode, used to exclude the presence of interposing vessels between transducer and target lesions; c) EUS fine needle aspiration (FNA) of the tumor in the caudate lobe, adjacent to the inferior vena cava; d) FNA – liver metastasis of a low grade neuroendocrine tumor. A. Nests of monotonous small cells, with scant cytoplasm and salt and pepper chromatin (Hematoxylin and Eosin stain, X 40). B. Tumor cells are positive for anti-cytokeratin AE1/AE3 antibody (X 40). C. Intense and diffuse staining of the cytoplasm with anti-chromogranin antibody (X 40). D. Tumor cells show strong cytoplasmic positivity for synaptophysin (X 40).
If the patient presented an extrahepatic tumor pre- sumed to be the primary one, or lesions in another organs of lymph nodes suspected to be metastasis, we performed FNA also from those tumors or suspected metastasis sites in the same session.
All patients were admitted and followed for compli- cations for at least 2 days.
Immunohistochemistry staining was performed at pa- thologist’s choice, after haematoxilin-eosin stains could not establish the diagnosis.
Statistical analysis
Nonparametric data are presented by mean and range.
The diagnostic yield was calculated as the number of bi- opsies that resulted in a diagnosis divided by the total number of biopsies performed. To investigate whether there was a statistically significant difference between diagnostic accuracy of EUS-FNA of the left lobe and right lobe, we performed a categorical Chi-squared con- tingency analysis.
Results
In 47/48 of patients, the results of EUS-FNA were positive for malignancy, while in one case the acquired fragment was inadequate. Diagnostic yield was 0.98 in our study.
The final diagnosis for the 48 liver biopsies is record- ed in Table I.
Characteristics of EUS examination
Multiple liver lesions were found in 77% of the pa- tients while 23% had a single lesion. Out of all biopsies, 83% were taken from the left lobe and 17% from the
right lobe. Statistical analysis comparing the diagnostic accuracy of the right and left lobe lesions biopsy results provided no statistically significant difference (p=0.723).
We also performed EUS-FNA of the primary tumor in 27/48 (56%) of patients while in 18/48 (38%) cases it was not possible due to poor accessibility or high procedural risk and in 3 (6%) cases the fragment was inadequate for diagnosis. In 35% of patients concurrent sampling of oth- er sites in addition to the liver and/or primary tumor was performed. Thus, we performed EUS-FNA from lymph nodes (12 cases), adrenal gland (1 case), lung (1 case), prostate (1 case – by lower EUS), ascites (1 case) and vertebra (1 case). All the extrahepatic FNAs were posi- tive for malignancy and the results correlated with the liver biopsy and with the primary tumor biopsy.
In addition to histology fragment immersed in for- malin, cytology smears were examined in 5/48 patients, with a positive result for malignancy in 3/5 cases and without elements of malignancy in 2/3 cases. Immuno- histochemistry staining was realized in 77% of cases, when haematoxilin-eosin stains could not establish the diagnosis.
The median number of passages was 2 (range: 1–4).
We reported no immediate or long-term complica- tions.
Discussion
In our study EUS-guided focal liver lesions biopsy using 22G needle provided an excellent diagnostic yield (0.98) with a small number of passes (median 2). We also performed, in the same sessions, FNA from other sites (in 35% of the cases) confirming malignancy in all cases.
Focal liver lesions are often discovered incidentally during an imaging test, such as US, CT or MRI. In other scenarios they are found in patients with risk factors for hepatic malignancy or during a preoperative staging of various malignancies. Detailed characterization of focal liver lesions represents an indispensable part of patient evaluation, as the presence or extent of liver involvement frequently changes the clinical stage and management.
In recent years, EUS-FNA has emerged as an alterna- tive tool in the diagnosis and classification of liver le- sions [14]. Most of the liver segments can be visualized with the echoendoscope and the proximity of the ultra- sound probe to the liver provides high-quality images of the liver parenchyma, which may have a decisive role in the detection, characterization and histological diagnosis of liver lesions [17,18]. Therefore, the utility of EUS and EUS-guided FNA of the liver lies in the ability to detect and diagnose cancer, and, in some cases, upstage the dis- ease and avoid surgery.
Table I. Histopathological diagnosis of the hepatic lesions ob- tained after EUS-FNA.
Diagnosis Number (%)
Metastatic liver lesions
Pancreatic adenocarcinoma 13 (27) Pulmonary adenocarcinoma 4 (8)
Mammary carcinoma 3 (6)
Neuroendocrine tumor 3 (6)
Colon adenocarcinoma 3 (6)
Gastric adenocarcinoma 2 (4)
Prostate adenocarcinoma 2 (4)
Small cell lung carcinoma 1 (5)
Endometrial carcinoma 1 (5)
Squamous cell carcinoma of the lung 1 (5) Primitive liver malignancies
Cholangiocarcinoma 8 (17)
Hepatocellular carcinoma 6 (13)
Non-diagnostic 1(2)
Total 48 (100)
There are a number of findings that highlight this study. The first is the overall excellent pathologic diag- nostic rate of 98% obtained using this procedure. Previ- ously published prospective studies with similar cohorts found diagnostic yields ranging from 82% to 94% [19- 27]. Secondly, in 17 out of the 33 patients with meta- static liver lesions, the biopsy from the primary tumor could not be performed. These were the cases with pre- vious surgically removal of the primary tumor and now presented for late relapse or when the biopsy from the primary tumor was considered to have a high procedural risk. We had also 3 patients in which the primary tumor biopsy was non-diagnostic. In their cases, EUS-FNA had a significant impact, and they could avoid additional di- agnostic procedures. Thirdly, our data demonstrate the versatility of the EUS approach. We diagnosed 13 differ- ent types of tumors, some of them not being traditionally diagnosed through EUS-FNA.
Concurrent biopsies of metastatic sites, other than the liver, during a single endoscopic procedure are another example of this versatility [28-30]. We were able to take a biopsy from the retroperitoneal lymph nodes, adrenal glands, lungs, vertebra and prostate. This procedure al- lows critical staging information to be obtained simul- taneously when establishing a primary diagnosis, thus expediting the management of a group with difficult to diagnose neoplasms.
The cytological examination was performed in addi- tion to the histology in 5/48 cases. Out of those, 2 were inconclusive, while 3 had signs of malignancy, but could not be properly characterized. Cytology could have been useful if rapid on-site evaluation (ROSE) would have been available [31] and in cases where it was not pos- sible to procure a histology specimen, and usually offers an incomplete diagnosis.
Anatomy limits the use of EUS FNA to the whole liver. The hilum, the left and proximal right lobe includ- ing the major portion of the intrahepatic biliary tract can be targeted by EUS. The caudate lobe masses can be also addressed and this is important as the percutane- ous biopsy is challenging due to its anatomic location [32,33]. We had no case in which the biopsy could not be performed because of the location of the tumors, but this was probably related to the inclusion criteria. For example, we considered that patients with peripheral le- sion in the right lobe could undergo percutaneous biopsy.
Other elements must also be taken into consideration, such as contraindication to sedation or upper gastroin- testinal tract stenosis. The cost of the EUS-FNA nee- dles is higher than those of the percutaneous needles, therefore department resources and experience will also influence the decision, since there are no guidelines re-
garding the first option when multiple techniques are viable.
The most common scenario we encountered in clini- cal practice is that of a patient diagnosed with focal liver lesions via CT/MRI/US referred to our Department for biopsy. In some cases, the primary tumor was not found or was more difficult to biopsy than the metastatic liver lesions. The decision to choose between EUS guided liv- er biopsy and percutaneous liver biopsy takes into con- sideration the size of the lesion (small lesions are more difficult to biopsy percutaneously than EUS guided), co- agulation status (many patients with liver lesions have an altered coagulation status and EUS-FNA has a lower bleeding risk), and the need for multiple biopsies (e.g.
pancreatic tumor with a focal liver lesion – biopsies can be performed from pancreas and liver at the same time).
In our study EUS-guided liver biopsy using 22G nee- dle provided an excellent diagnostic yield with a mini- mal number of passes (median 2, range 1-4). Studies that compared accuracy depending on the needle size for EUS-FNA of the liver focal lesions are scarce [34,35].
22G needles are preferred mainly due to greater flexibil- ity and easier passage. Data is mixed regarding this as- pect, and tissue adequacy seems to be higher for the 19G versus 22G needle because the latter one procures sam- ples that are more prone to fragmentation during speci- men processing [34,35]. However, it is still unclear if the diagnostic yield of the 19G needle is better, especially for focal liver lesions.
Complications and safety
EUS has a very good overall safety profile. Nonethe- less, there are notable complications, esophageal per- foration being the most serious of them [36]. However, the majority of complications related to EUS take place during EUS-FNA, and include infection, hemorrhage, bile peritonitis and exceptionally malignant seeding. A systematic review reported 0.02% mortality associated with EUS and EUS-FNA, while the overall rate of EUS- FNA-specific morbidity was 0.98% [37-39]. A 2019 systematic review on the subject of EUS-FNA of focal liver lesions found complication rates ranging from 0%
(6/8 studies) to 4% in one study [14]. In that particular study, Berge et al reported complications in 6 patients (4%) from which 1 death (suspected to have an occluded biliary stent at the time of EUS), 1 bleeding, 2 cases of post-procedural fever and 2 cases of post-procedural ab- dominal pain occurred [20]. In our study, there were no immediate or long term complications. To date, no occur- rences of tumor seeding after EUS-FNA for liver metas- tases were reported [27].
Our study has some limits. First, it was a single-arm observational study and did not compare the outcomes of EUS-FNA with those of percutaneous US/CT guided bi- opsy. Therefore, further comparative studies with a large number of patients are necessary to confirm the superior- ity of EUS-FNA for liver lesions. Secondly, the limita- tions of EUS-FNA of the liver have to be underlined. The presence of vascular structures in the path of the needle may limit the access to the lesion. Nevertheless, with improving resolution, use of Doppler US, elastography [40], harmonic imaging and/or contrast enhancement [41] have improved the accuracy of the procedure.
Conclusion
The results of our study show that EUS-FNA of the focal liver lesions is a safe procedure, with high accu- racy for the diagnosis of malignancy. Although EUS has not traditionally been used in the evaluation of the liver, EUS-FNA can be helpful for malignant liver mass diagnosis, especially in cases where the percutaneous ap- proach is difficult.
Conflicts of interest: none References
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