**5. Current recommendations regarding conditions that require liver biopsy**

The indications for liver biopsy were greatly reduced since the recent introduction of accu‐ rate non-invasive tests which can evaluate liver parenchyma with minimal or no patient trauma. The concept of liver biopsy may evolve even further, if in vivo direct histological methods such as pCLE will provide important additional data. It is most likely that the rec‐ ommendations for liver biopsy will suffer further changes in following years. A series of these advancements will be discussed separately within this chapter. Below, we will de‐ scribe some of the main indications for liver biopsy, either for diagnostic purposes or for evaluating and staging liver disease.

#### **5.1. Grading and staging of chronic viral hepatitis**

**4. Risks, complications and post-procedural complaints of liver biopsies**

The main risks for a patient subjected to liver biopsy were already briefly discussed in the previous paragraphs. Their frequency and predisposition in certain patient groups are de‐ terminant factors for choosing one biopsy technique in favor of another. The risk of bleeding cannot be excluded with any instrument, and liver biopsy is not recommended in most cases of suspected primary liver cancers because of a needle track seeding of tumor cells. These however do not exclude liver biopsy as a last resort diagnostic tool, when imagistic or serum

The most commonly occurring complication of percutaneous liver biopsy is pain, present in up to 84% of procedures and ranging from mild discomfort to severe pain [28]. It is usually located in the right upper quadrant and it is referred to the right shoulder, with various in‐ tensities and time of installment. Moderate to severe pain is present in fewer than 5% of all patients, and may be the sign of a more severe complication such as bleeding or the punc‐ turing of the gallbladder [16, 29]. Mechanisms that lead to pain after the biopsy maneuver are not fully understood, however it is likely to be caused by bile or blood extravasation with subsequent capsule swelling (the only liver component with sensitive nervous termina‐ tions) [30]. Another cause of upper abdominal pain is the traction of the falciform ligament after the puncture. Cervical pain, as well as pain in the right shoulder, may also be caused by the irritation of the phrenic nerve. Subcapsular hematoma may lead to respiratory pain and irritation of the pleura or peritoneum may lead to vagal stimulation and consecutive va‐ gal shock, manifested through bradycardia, severe hypotension, weak pulse and intense pain in the upper abdomen [1]. In some cases of extreme pain, hospitalization and further

imaging tests are required to determine the correct course of action for these patients.

ator experience, the diameter of the needles and their diameter [16].

However, the most important complication of liver biopsy is bleeding. The most severe bleedings occur intraperitoneally, when they determine a drop in vital signs and can be vi‐ sualized through imaging [16, 31]. Urgent hospitalization and blood transfusion, even fol‐ lowed by surgery or radiological intervention may be required. Nevertheless, these cases are scarce, with 1 in 2 500 up to 10 000 biopsies incidence, while less severe cases which do not require blood transfusions or surgical maneuvers are more frequent, approximately 1 in 500 biopsies [16]. Serious bleeding-related complications usually occur within 2 hours of the procedure, and over 90% of all bleedings become evident within 24 hours of the procedure. Clinical symptoms are revelatory, as patients experience hypotension and shock. Age and the underlying conditions also are predictive factors, as older patients and liver masses are more frequently associated with post-puncture bleeding. A correlation between the needle type and the risk for bleeding was also cited in literature, as cutting needle seem to pose an increased risk compared to their suction counterparts [15]. Other factors are related to oper‐

A correlation between conventional coagulation tests and the risk of bleeding has not been sufficiently demonstrated until now; therefore no certain recommendations in this regard are currently in place [16]. The option to insert coagulation agents on the needle tract is con‐ sidered, especially in the US, with no definite data on its ability to prevent possible bleed‐

tests proved constantly inconclusive or do not converge to an outcome.

90 Liver Biopsy – Indications, Procedures, Results

The recent outburst of viral hepatitis cases (especially as a result of the increasing number of newly diagnosed virus C infections) represents a major health burden worldwide. With al‐ most four million people being infected in the United States alone, and between 130 and 170 million worldwide, chronic hepatitis C virus (HCV) infections and more than double those figures for hepatitis B virus (HBV) infections, this ensemble of viral diseases currently repre‐ sent the main cause of liver-related morbidity [33, 34].

Nowadays, the role of liver histology in the positive diagnosis of chronic viral hepatitis has greatly diminished. However, it still plays a central role when assessing both activity and progression of the disease [8, 35]. Sampling issues arise when evaluating liver parenchyma affected by chronic hepatitis, as the quality of the obtained specimens can greatly influence the semi-quantitative scores developed in the last four decades to quantify disease progres‐ sion. There are a number of changes present within the liver and their heterogeneity makes the "10-complete portal spaces" paradigm essential when evaluating disease severity. All scoring systems are bound to yield significantly different results, primarily because of sam‐ ple variability, but also as a result of the different levels of expertise from the pathologist involved in their evaluation. All modifications of the liver parenchyma – inflammation, ne‐ crosis or fibrosis – exhibit particularities and can be subjectively interpreted even in a scor‐ ing system [8].

Currently, even though liver biopsy is still regarded as the "gold standard" when diagnos‐ ing these conditions, no consensus has been reached. Liver biopsy remains therefore a con‐ troversial decision which ultimately has to be performed only when a clear diagnosis cannot

Risks and Benefits of Liver Biopsy in Focal Liver Disease

http://dx.doi.org/10.5772/52620

93

Diseases that determine intrahepatic iron accumulation are the main indications for liver bi‐ opsy when a metabolic condition is suspected, besides NAFLD or ALD. Hereditary hemo‐ chromatosis, in its various forms identified today, is routinely diagnosed and staged through liver biopsy [8, 39]. The metabolic syndrome (syndrome X) represents the increased accumulation of iron within hepatocytes, in the context of NAFLD. These deposits are not distributed equally among various regions of the liver, therefore deeper biopsies are needed in order to collect more tissue for analysis [8, 40]. For this purpose, at least two scores are currently used – the Deugnier and the Brissot scores [41, 42]. The hepatic iron index is calcu‐ lated through a mathematical formula which takes into account the hepatic iron concentra‐ tion (evaluated by liver biopsy), its atomic weight as well as the age of the patients. An index above 1.9 is an indicator of hemochromatosis; however its sensitivity is low as it is de‐

Discovery of a focal liver lesions (FLL) can occur after imaging tests used routinely for either screening or diagnosis. The practitioner may encounter lesions of various sizes, number and location, some of them being associated with pre-existing conditions. This is especially the case of primary liver malignant tumors, either hepatocellular carcinoma (HCC) or cholan‐ gyocarcinoma (CC). Early discovery of a FLL is possible in up to 60% of all cases, especially in developed countries where surveillance programs are well established and health serv‐ ices are available to the majority of the population, irrespective of their location and eco‐

Imaging alone is currently the main diagnostic procedure for HCC, as modern contrast-en‐ hanced techniques, either by CT or MRI, are sufficient to highlight the hallmark pattern of tumor vascularization. Diagnostic criteria in the United States of America, Europe and Asia stipulate that imaging techniques are sufficient to diagnose the majority of HCC lesions, bi‐ opsy being reserved for the few situations where imaging is unclear, discordance between two methods exists, or tumor size does not allow a precise imaging diagnosis [43–45]. A de‐ fining criteria for evaluating FLLs is the presence of an underlying hepatic condition such as

When HCC is suspected in cirrhotic patients, criteria for liver biopsy are set by the size of the tumor. In nodules between 1 and 2 centimeters, diagnosis should ideally be based on non-invasive criteria; however, confirmation through biopsy should be sought whenever possible. The evaluation should be performed ideally by a pathologist with extensive experi‐ ence in evaluating liver biopsies. In case of inconclusive findings after the initial biopsy, a

be extracted from serum values, imagistic findings and clinical features [38].

**5.3. Metabolic liver disease**

**5.4. Focal liver lesions**

nomic status [43, 44].

hepatitis or cirrhosis.

pendent on the timing of the liver biopsy [8].

The first approach to liver biopsy scoring for chronic hepatitis dates from the early 1980s when the histological activity index (HAI) was introduced by Knodell and Ishak [21]. This model did not clearly delimited between disease grades (that is, the importance of any in‐ flammatory activity present) and stage, which refers to the degree of fibrosis and parenchy‐ mal remodeling. The later modification performed by Ishak resolves most of these issues and is currently used worldwide, partially replacing or at least complementing the earlier alternative Knodell classification. The preferred approach is a parallel evaluation using sev‐ eral scoring methods, such as the modified HAI, the Scheuer or the Ludwig systems and the Knodell classification, or the METAVIR algorithm devised in France [23].

#### **5.2. Abnormal hepatic biochemical tests, alcoholic and non-alcoholic liver disease**

Chronically elevated hepatic biochemical parameters are a common concern for many pa‐ tients during routine screenings or general consults. Gastroenterologists facing abnormal as‐ partate aminotransferase/alanine aminotransferase, gamma-glutamyltransferase or alkaline phosphatase levels have to conduct a thorough anamnesis to determine the underlying con‐ dition. Many such patients either acknowledge high alcohol consumption or are diagnosed with non-alcoholic liver disease (NAFLD) associated with their lifestyle, while few remain undiagnosed until they begin to display signs of liver cirrhosis (cryptogenic cirrhosis or cir‐ rhosis of unknown etiology). The latter two classes are usually diagnosed through liver bi‐ opsy, as no other condition can be found from either their background or non-invasive investigations and blood tests [8, 16].

The most common aspect revealed by liver biopsy in these patients is macrovesicularsteato‐ sis, intracellular lipid accumulation exceeding 5% of the total cellular population. This mac‐ rosteatosis is generally coined as fatty liver disease (FLD) and can either be identified as either alcoholic liver disease (ALD), when regular alcohol consumption above established thresholds is established, or NAFLD when obesity, type 2 diabetes mellitus and/or hyperli‐ pidemia are associated. Steatohepatitis, either of alcoholic origin (alcoholic steatohepatitis – ASH) or metabolic (non-alcoholic steatohepatitis – NASH) share histological similarities. NASH is recognized as a form of NAFLD with ballooning hepatocytes and necroinflamma‐ tory changes, as well as fibrosis and parenchymal remodeling. The NAFLD activity score (NAS) was developed in an attempt to objectively quantify the extension of this disease. This score sums the three pathologic features – steatosis, lobular inflammation and hepato‐ cellular ballooning on a 0 to 8 scale, 5 being the cut-off point for a certain diagnose of NASH and 3–4 being labeled as borderline steatohepatitis [36, 37].

Currently, even though liver biopsy is still regarded as the "gold standard" when diagnos‐ ing these conditions, no consensus has been reached. Liver biopsy remains therefore a con‐ troversial decision which ultimately has to be performed only when a clear diagnosis cannot be extracted from serum values, imagistic findings and clinical features [38].

#### **5.3. Metabolic liver disease**

the semi-quantitative scores developed in the last four decades to quantify disease progres‐ sion. There are a number of changes present within the liver and their heterogeneity makes the "10-complete portal spaces" paradigm essential when evaluating disease severity. All scoring systems are bound to yield significantly different results, primarily because of sam‐ ple variability, but also as a result of the different levels of expertise from the pathologist involved in their evaluation. All modifications of the liver parenchyma – inflammation, ne‐ crosis or fibrosis – exhibit particularities and can be subjectively interpreted even in a scor‐

The first approach to liver biopsy scoring for chronic hepatitis dates from the early 1980s when the histological activity index (HAI) was introduced by Knodell and Ishak [21]. This model did not clearly delimited between disease grades (that is, the importance of any in‐ flammatory activity present) and stage, which refers to the degree of fibrosis and parenchy‐ mal remodeling. The later modification performed by Ishak resolves most of these issues and is currently used worldwide, partially replacing or at least complementing the earlier alternative Knodell classification. The preferred approach is a parallel evaluation using sev‐ eral scoring methods, such as the modified HAI, the Scheuer or the Ludwig systems and the

Knodell classification, or the METAVIR algorithm devised in France [23].

**5.2. Abnormal hepatic biochemical tests, alcoholic and non-alcoholic liver disease**

Chronically elevated hepatic biochemical parameters are a common concern for many pa‐ tients during routine screenings or general consults. Gastroenterologists facing abnormal as‐ partate aminotransferase/alanine aminotransferase, gamma-glutamyltransferase or alkaline phosphatase levels have to conduct a thorough anamnesis to determine the underlying con‐ dition. Many such patients either acknowledge high alcohol consumption or are diagnosed with non-alcoholic liver disease (NAFLD) associated with their lifestyle, while few remain undiagnosed until they begin to display signs of liver cirrhosis (cryptogenic cirrhosis or cir‐ rhosis of unknown etiology). The latter two classes are usually diagnosed through liver bi‐ opsy, as no other condition can be found from either their background or non-invasive

The most common aspect revealed by liver biopsy in these patients is macrovesicularsteato‐ sis, intracellular lipid accumulation exceeding 5% of the total cellular population. This mac‐ rosteatosis is generally coined as fatty liver disease (FLD) and can either be identified as either alcoholic liver disease (ALD), when regular alcohol consumption above established thresholds is established, or NAFLD when obesity, type 2 diabetes mellitus and/or hyperli‐ pidemia are associated. Steatohepatitis, either of alcoholic origin (alcoholic steatohepatitis – ASH) or metabolic (non-alcoholic steatohepatitis – NASH) share histological similarities. NASH is recognized as a form of NAFLD with ballooning hepatocytes and necroinflamma‐ tory changes, as well as fibrosis and parenchymal remodeling. The NAFLD activity score (NAS) was developed in an attempt to objectively quantify the extension of this disease. This score sums the three pathologic features – steatosis, lobular inflammation and hepato‐ cellular ballooning on a 0 to 8 scale, 5 being the cut-off point for a certain diagnose of NASH

ing system [8].

92 Liver Biopsy – Indications, Procedures, Results

investigations and blood tests [8, 16].

and 3–4 being labeled as borderline steatohepatitis [36, 37].

Diseases that determine intrahepatic iron accumulation are the main indications for liver bi‐ opsy when a metabolic condition is suspected, besides NAFLD or ALD. Hereditary hemo‐ chromatosis, in its various forms identified today, is routinely diagnosed and staged through liver biopsy [8, 39]. The metabolic syndrome (syndrome X) represents the increased accumulation of iron within hepatocytes, in the context of NAFLD. These deposits are not distributed equally among various regions of the liver, therefore deeper biopsies are needed in order to collect more tissue for analysis [8, 40]. For this purpose, at least two scores are currently used – the Deugnier and the Brissot scores [41, 42]. The hepatic iron index is calcu‐ lated through a mathematical formula which takes into account the hepatic iron concentra‐ tion (evaluated by liver biopsy), its atomic weight as well as the age of the patients. An index above 1.9 is an indicator of hemochromatosis; however its sensitivity is low as it is de‐ pendent on the timing of the liver biopsy [8].

#### **5.4. Focal liver lesions**

Discovery of a focal liver lesions (FLL) can occur after imaging tests used routinely for either screening or diagnosis. The practitioner may encounter lesions of various sizes, number and location, some of them being associated with pre-existing conditions. This is especially the case of primary liver malignant tumors, either hepatocellular carcinoma (HCC) or cholan‐ gyocarcinoma (CC). Early discovery of a FLL is possible in up to 60% of all cases, especially in developed countries where surveillance programs are well established and health serv‐ ices are available to the majority of the population, irrespective of their location and eco‐ nomic status [43, 44].

Imaging alone is currently the main diagnostic procedure for HCC, as modern contrast-en‐ hanced techniques, either by CT or MRI, are sufficient to highlight the hallmark pattern of tumor vascularization. Diagnostic criteria in the United States of America, Europe and Asia stipulate that imaging techniques are sufficient to diagnose the majority of HCC lesions, bi‐ opsy being reserved for the few situations where imaging is unclear, discordance between two methods exists, or tumor size does not allow a precise imaging diagnosis [43–45]. A de‐ fining criteria for evaluating FLLs is the presence of an underlying hepatic condition such as hepatitis or cirrhosis.

When HCC is suspected in cirrhotic patients, criteria for liver biopsy are set by the size of the tumor. In nodules between 1 and 2 centimeters, diagnosis should ideally be based on non-invasive criteria; however, confirmation through biopsy should be sought whenever possible. The evaluation should be performed ideally by a pathologist with extensive experi‐ ence in evaluating liver biopsies. In case of inconclusive findings after the initial biopsy, a second one should be performed if no other imaging criteria are present during the evalua‐ tion period. Nodules larger than 2 centimeters discovered through routine US should be ide‐ ally diagnosed through non-invasive procedures; however, when radiological findings are atypical, a liver biopsy should be obtained as confirmation [43–45]. A panel of immunohisto‐ chemical markers was proposed as diagnostic when evaluating liver biopsies for HCC. A combination of glypican 3, heat shock protein 70 and glutamine synthetase are recommend‐ ed for the differential diagnosis between early HCC and high grade dysplastic nodules [46] (Di Tomaso et al, 2009). A final recommendation of the EASL-EORTC guidelines is that liver biopsy should be performed within controlled settings of scientific research, for identifying new markers for HCC and for tissue bio-banking[44].

sy is performed. This diagnosis is often not possible on cross-sectional imaging studies as well as tumor serum markers, as their specificity for such lesions is inadequate. An expert hepatologist should closely collaborate with an experimented pathologist, as the diagnosis is difficult most of the times. These lesions may develop in the presence of an underlying liver condition, which would aid the clinical diagnosis or suspicion on the part of the

Risks and Benefits of Liver Biopsy in Focal Liver Disease

http://dx.doi.org/10.5772/52620

95

The majority of lesions discovered through imaging techniques in patients without pre-ex‐ isting liver conditions are benign in origin, mostly solitary or occasionally multiple. They ex‐ hibit particular vascular patterns in contrast-enhanced imaging techniques and are thus easily diagnosed without the use of invasive techniques. Such is the case of liver hemangio‐ mas, mostly solitary benign tumors with characteristic contrast enhancement throughout all phases of an imaging investigation. Other lesions such as focal nodular hyperplasia are also usually solitary and may display distinct features such as "central scarring" or particular en‐ hancement patterns (spiked wheel enhancement etc.). All these particularities have a mor‐ phological substrate: central hypoechoic areas which do not show vascular hyperenhancement usually correspond to areas of necrosis; intense signal enhancement zones are indicators of high microvessel density and neo-angiogenesis vessels; the US or CT

Overall, lesions may present as cystic, solid or vascular; all these particularities usually be‐ ing identified through non-invasive procedures prior to liver biopsy. In the USA for in‐ stance, liver biopsy is performed by imagists as they can perform the pre-biopsy or real-time assessment of the procedure, while in Europe most gastroenterologists or hepatologists per‐ form the procedure themselves, under US surveillance [43, 44]. A core biopsy is usually pre‐ ferred to fine-needle aspiration, as histology is considered superior from a diagnostic perspective compared to cytology; another reason being that experts in evaluating histology are more numerous compared to cytologists. The risk of puncturing blood vessels, either major arteries in the normal parenchyma, or intra-tumoral vessels is considerably diminish‐ ed by real-time imaging guidance, for instance US with color Doppler. The risk of track seeding exists, even if extremely low (one study estimates a risk of 0.13%, while in other studies no such incidents were reported) [48, 49]. A certain dependency on the technique and size of the needle was also proven [50]. Infectious lesions may be biopsied; even if echi‐ nococcal cysts were considered an absolute contraindication as puncturing can be associated with anaphylactic shock and death, it was proven that these lesions can be aspirated with 19

peripheral rim translate in certain particularities of fibrous capsules [1, 16, 44].

or 22-gauge needles, taking all preparations for possible anaphylaxis [51].

**6.1. Probe-based confocal laser endomicroscopy**

**6. Novel techniques in liver biopsy; modern non-invasive alternatives**

The latest development in histological evaluation of gastrointestinal structures is confocal la‐ ser endomicroscopy. It allows for the in vivo evaluation of dysplasia and malignancies of the gastrointestinal tract, or in order to obtain directed biopsies that would allow rapid and

clinician [1, 16].

The current tendency in diagnostic medicine is to avoid liver biopsy when evaluating HCC [44]. The main reasons against performing liver biopsy are the high rate of sampling errors which would diminish the sensitivity of the investigation; a higher rate of recurrence posttransplant in patients who underwent liver biopsy and finally the small but well-established risk of needle track seeding. In transplant referral centers, liver biopsy is performed more frequently, as there is an increased need for a correct final diagnosis; however, these proce‐ dures are subject to wide variation depending on country-specific regulations [43, 44]. An‐ other argument for liver biopsy in HCC cases that benefit from chemotherapy would be the importance of histological grading. Response to local or systemic anti-angiogenic or antiproliferative agents might be dictated by the microscopic configuration of the tumor and the amount of angiogenesis markers present on histological samples [16].

The second most important primary liver malignancy is CC. It can also develop in the pres‐ ence of an underlying liver condition, such as chronic biliary tract diseases. Imaging diagno‐ sis is sometimes difficult, as it may present similar contrast-enhancing patterns to those of HCC – the majority of CCs are solitary masses present in the hilum, while a minority can develop in other regions [43, 44]. Mixed forms of CC/HCC may also be present, their noninvasive diagnosis being even more difficult. All these forms of either atypical CCs or mixed presentations are usually subjected (with various degrees of variability, depending on set‐ ting and context) to liver biopsy. Surgical intervention, either by resection or liver trans‐ plant, are the approaches that yield the best survival chances for the patient. Therefore, liver biopsy may be indicated, as well as concomitant biopsy of lymph nodes in the upper ab‐ dominal area [16].

Metastases have the overall highest incidence amongst malignant liver lesions [47]. When a secondary malignant liver lesion is suspected and the physician cannot identify the primary point, liver biopsy is usually diagnostic, even when imaging fails to provide enough detail. If an underlying parenchymal disease is also suspected, biopsy should be performed outside the lesion site as well, for an extended and more precise diagnosis. A vast panel of markers may be employed in an immunohistochemistry study; however, the histologic architecture identified through normal techniques may be sufficient for an expert pathologist to deter‐ mine the primary site of origin [1, 16].

Other rare primary liver parenchyma or bile duct malignant or benign neoplasms can ulti‐ mately be identified through histological analysis, after careful imaging-guided liver biop‐ sy is performed. This diagnosis is often not possible on cross-sectional imaging studies as well as tumor serum markers, as their specificity for such lesions is inadequate. An expert hepatologist should closely collaborate with an experimented pathologist, as the diagnosis is difficult most of the times. These lesions may develop in the presence of an underlying liver condition, which would aid the clinical diagnosis or suspicion on the part of the clinician [1, 16].

second one should be performed if no other imaging criteria are present during the evalua‐ tion period. Nodules larger than 2 centimeters discovered through routine US should be ide‐ ally diagnosed through non-invasive procedures; however, when radiological findings are atypical, a liver biopsy should be obtained as confirmation [43–45]. A panel of immunohisto‐ chemical markers was proposed as diagnostic when evaluating liver biopsies for HCC. A combination of glypican 3, heat shock protein 70 and glutamine synthetase are recommend‐ ed for the differential diagnosis between early HCC and high grade dysplastic nodules [46] (Di Tomaso et al, 2009). A final recommendation of the EASL-EORTC guidelines is that liver biopsy should be performed within controlled settings of scientific research, for identifying

The current tendency in diagnostic medicine is to avoid liver biopsy when evaluating HCC [44]. The main reasons against performing liver biopsy are the high rate of sampling errors which would diminish the sensitivity of the investigation; a higher rate of recurrence posttransplant in patients who underwent liver biopsy and finally the small but well-established risk of needle track seeding. In transplant referral centers, liver biopsy is performed more frequently, as there is an increased need for a correct final diagnosis; however, these proce‐ dures are subject to wide variation depending on country-specific regulations [43, 44]. An‐ other argument for liver biopsy in HCC cases that benefit from chemotherapy would be the importance of histological grading. Response to local or systemic anti-angiogenic or antiproliferative agents might be dictated by the microscopic configuration of the tumor and the

The second most important primary liver malignancy is CC. It can also develop in the pres‐ ence of an underlying liver condition, such as chronic biliary tract diseases. Imaging diagno‐ sis is sometimes difficult, as it may present similar contrast-enhancing patterns to those of HCC – the majority of CCs are solitary masses present in the hilum, while a minority can develop in other regions [43, 44]. Mixed forms of CC/HCC may also be present, their noninvasive diagnosis being even more difficult. All these forms of either atypical CCs or mixed presentations are usually subjected (with various degrees of variability, depending on set‐ ting and context) to liver biopsy. Surgical intervention, either by resection or liver trans‐ plant, are the approaches that yield the best survival chances for the patient. Therefore, liver biopsy may be indicated, as well as concomitant biopsy of lymph nodes in the upper ab‐

Metastases have the overall highest incidence amongst malignant liver lesions [47]. When a secondary malignant liver lesion is suspected and the physician cannot identify the primary point, liver biopsy is usually diagnostic, even when imaging fails to provide enough detail. If an underlying parenchymal disease is also suspected, biopsy should be performed outside the lesion site as well, for an extended and more precise diagnosis. A vast panel of markers may be employed in an immunohistochemistry study; however, the histologic architecture identified through normal techniques may be sufficient for an expert pathologist to deter‐

Other rare primary liver parenchyma or bile duct malignant or benign neoplasms can ulti‐ mately be identified through histological analysis, after careful imaging-guided liver biop‐

new markers for HCC and for tissue bio-banking[44].

94 Liver Biopsy – Indications, Procedures, Results

dominal area [16].

mine the primary site of origin [1, 16].

amount of angiogenesis markers present on histological samples [16].

The majority of lesions discovered through imaging techniques in patients without pre-ex‐ isting liver conditions are benign in origin, mostly solitary or occasionally multiple. They ex‐ hibit particular vascular patterns in contrast-enhanced imaging techniques and are thus easily diagnosed without the use of invasive techniques. Such is the case of liver hemangio‐ mas, mostly solitary benign tumors with characteristic contrast enhancement throughout all phases of an imaging investigation. Other lesions such as focal nodular hyperplasia are also usually solitary and may display distinct features such as "central scarring" or particular en‐ hancement patterns (spiked wheel enhancement etc.). All these particularities have a mor‐ phological substrate: central hypoechoic areas which do not show vascular hyperenhancement usually correspond to areas of necrosis; intense signal enhancement zones are indicators of high microvessel density and neo-angiogenesis vessels; the US or CT peripheral rim translate in certain particularities of fibrous capsules [1, 16, 44].

Overall, lesions may present as cystic, solid or vascular; all these particularities usually be‐ ing identified through non-invasive procedures prior to liver biopsy. In the USA for in‐ stance, liver biopsy is performed by imagists as they can perform the pre-biopsy or real-time assessment of the procedure, while in Europe most gastroenterologists or hepatologists per‐ form the procedure themselves, under US surveillance [43, 44]. A core biopsy is usually pre‐ ferred to fine-needle aspiration, as histology is considered superior from a diagnostic perspective compared to cytology; another reason being that experts in evaluating histology are more numerous compared to cytologists. The risk of puncturing blood vessels, either major arteries in the normal parenchyma, or intra-tumoral vessels is considerably diminish‐ ed by real-time imaging guidance, for instance US with color Doppler. The risk of track seeding exists, even if extremely low (one study estimates a risk of 0.13%, while in other studies no such incidents were reported) [48, 49]. A certain dependency on the technique and size of the needle was also proven [50]. Infectious lesions may be biopsied; even if echi‐ nococcal cysts were considered an absolute contraindication as puncturing can be associated with anaphylactic shock and death, it was proven that these lesions can be aspirated with 19 or 22-gauge needles, taking all preparations for possible anaphylaxis [51].
