Gut, 1987, 28, 237-241

Liver and biliary

Histologic differential diagnosis of focal liver lesionsby ultrasonically guided fine needle biopsyB LIMBERG, W W HOPKER, AND B KOMMERELL

From the Department ofInternal Medicine, Department of Pathology, University ofHeidelberg, Heidelberg,FRG

SUMMARY Ultrasonically guided fine needle biopsies were carried out in 84 patients with focal liverlesions and were subsequently evaluated histologically. A correct diagnosis of malignancy wasmade in 46 of 52 patients with proven hepatic malignancy, showing an overall accuracy of93%. Thespecificity of the procedure was 100%. Such histological examination not only enables thedifferentiation between primary and secondary hepatic malignancy; it has the additional advantageof making a more precise tumour description and at the same time it pinpoints the primary site ofthe tumour.

Imaging techniques such as dynamic ultrasound orcomputed tomography provide high resolutionsectional images of focal liver lesions. It is notpossible with a clinically acceptable degree ofaccuracy to distinguish between benign and malig-nant lesions with any of these imaging modalities, foran exact diagnosis a cytological or histological exami-nation is necessary. Fine needle biopsy of the liverhas been shown, to be a safe and accurate method forthe cytological diagnosis of cancer; the diagnosticyield has been reported to be from 84-95%.' Thedifferentiation between primary and secondaryhepatic malignancy, however, requires histologicalexamination. Moreover, diagnosis of hepatocellularcarcinoma cannot easily be accomplished by cyto-logical examination alone, because regeneratinghepatocytes - for example, in hepatitis or activecirrhosis, may show changes mimicking hepatocellu-lar carcinoma.'On fine needle histological sampling tissue frag-

ments are obtained, making possible a histologicaldiagnosis with a more precise tumour description.The purpose of our study was to examine thedifferential diagnostic value of ultrasonically guidedfine needle aspiration combined with histological

Address for correspondcncc: PD Dr Bernd Limberg. Medizinische Universi-i.itsklinik. Bergheimerstr 5X8 D-690(0 iIcidelhcrg, Federal Republic ofGermany.Received for publication 13 June 1986.

examination of the aspirated material in patients withsuspected hepatic malignancy and focal hepaticlesions.

Methods

PATIENTS

Ultrasonically guided fine needle biopsies werecarried out on 84 patients (average age: 59 years).Biopsies were done for the following indications: toverify the presence of liver metastases in patientswith known malignant disease in order to determinethe correct stage of the disease, to determine thenature of the primary tumour in patients withsuspected hepatic malignancy and occult malignantdisease, and to differentiate between malign andbenign focal lesions with equivocal focal echopatterns.

Biopsies were obtained using a commercially avail-able needle with an outer diameter of 0.9 mm (20gauge; Braun Melsungen; TSK-Supra). The ultra-sound guided biopsies were done freehand. A 20 ccsyringe containing 0-9% NaCI was attached to theneedle. After local anaesthesia, the needle wasintroduced close to the transducer and visualised as itentered the sound field and was then introduced intothe focal hepatic lesion. The needle was quicklymoved back and forth several times during maximalaspiration. Three or four passes were made in eachpatient. The diameter of the focal hepatic lesions

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varied from 1.5 to 13 cm (mean: 3-9 cm). In cysticlesions the fluid was aspirated and a biopsy was takenfrom the tissue next to the cyst. Material suitable forhistological examination was obtained in 78 of 84patients. The tissue fragments were fixed in 5%unbuffered formalin, embedded in paraplast andwere stained by the Masson-Goldner, periodic acid-Schiff (PAS) and the haematoxylin-eosin technique.The diagnosis of malignant liver disease was con-

sidered proven when confirmatory tissue wasobtained by surgery or at necropsy, or when theclinical course of the disease showed a malignancy.The diagnosis of benign focal liver lesion was con-sidered correct when additional biochemical, radio-logic, and endoscopic methods as well as the sono-graphic follow up and the clinical course of thedisease over two years excluded a malignant diseaseof the liver. The diagnosis of haemangioma wasconfirmed by angio-computed tomography and intwo cases by surgery. In patients with primarycarcinoma of the liver alpha-1-fetoprotein (AFP)serum concentration was determined routinely and insome cases a laparoscopy combined with a directlarge bore biopsy was undertaken.

Results

Fifty two of 84 patients who had undergone fineneedle biopsy had hepatic malignancy confirmed byother invasive procedures, and imaging methods, aswell as by the clinical course of the disease (Table 1).Fine needle biopsy results definitely proved to bepositive for malignant disease in 46 of the 52 patients.There were six false negative results, but there wereno false positive results; the overall accuracy was93%, and the specificity 100% (Table 2). Histologicalexamination gave a more precise tumour descriptionand with the exception of 10 cases a determination ofthe primary site of the tumour was possible (Figure).

In the current series where 15 patients havediagnostically proved hepatocellular carcinoma,raised serum AFP concentrations were the first clueto diagnosis in only 46% of the cases. In addition tofine needle biopsies, laparoscopies and large borebiopsies were carried out in six cases, but in thesecases neither the laparoscopies nor the biopsie con-firmed the diagnosis. In 13 out of these 15 patientswith proved hepatocellular carcinoma histologicalexamination of the ultrasonically guided fine needlebiopsies proved to be positive; in one patient thebiopsy was classified as negative, and in the other asadenoma (Table 3).

Thirty two of the 84 patients had a benign focalhepatic lesion (Table 4). In nine patients the diagno-sis of a hepatic cyst was confirmed by aspiration ofclear fluid; the biopsy taken from the neighbouring

tissue showed normal liver parenchyma. In sevencases initial minimal aspiration was followed by animmediate spurt of blood, at which time the pro-cedure was stopped and no further passes made intothe lesion. In only one of these seven cases coulda specimen for histological examination be taken.Aspiration of blood as well as the characteristicresults obtained from computed tomography pro-vided suggestive evidence of the presence ofhaemangioma. In nine patients biopsy specimens ofechogenic lesions were reported by the pathologist asconsistent with fatty infiltration of the liver and nomalignant cells were encountered. In these patientsother clinical and laboratory investigations and thefollow up revealed no clinical signs of malignantdisease. In two cases a resolving hepatitis wasdiagnosed and the subsequent sonographic changesover a period of months confirmed the diagnosis.

Discussion

Fine needle biopsy followed by cytologic examina-tion has been proved to be a reliable method for thediagnosis of hepatic malignancy. The diagnostic yieldhas been reported to be from 84-95%.`'- Nonethe-less the results of cytological examination are marredby the presence of false positives.78 Moreover, thedifferentiation between primary and secondaryhepatic malignancy is difficult by cytological exami-nation alone.9 In establishing a management plan for

Table 1 Sites ofprimary neoplasms in patients withmalignantfocal lesions

Primary tumour Patients (n)

Liver 15Stomach 4Colon 12Breast 4Bronchogenic 4Melanoma 2Hodgkin's 1Urinary bladder 1Pancreas 2Gall bladder 1Unknown primary 6Total 52

Table 2 Results ofhistologic examination ofultrasonicallyguidedfine-needle biopsies offocal liver lesions

Malignant lesionsTrue False

Positive Negative Positive Negative46/84 32/84 0/84 6/84

Overall accuracy: 93%; specificity: 100%.

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Table 3 Results offine needle biopsy, laparoscopy anddetermination ofserum Alpha-fetoprotein (A FP)concentrations in patients with proven hepatocellularcarcinoma (HCC)

Fine needle biopsy Laparoscopylbiopsy AFP (nglml)

1 HCC Cirrhosis 250()2 HCC Cirrhosis 123 HCC 504 HCC 1100)5 HCC Cirrhosis 10506 Cirrhosis 16207 HCC Chronic active hepatitis 108 HCC 99 HCC 1210 HCC 3111 HCC Chronic active hepatitis 4212 Adenoma 1913 HCC Cirrhosis 35()014 HCC 85015 HCC 980Positive 13/15 0/6 7/15

Table 4 Benignfocal hepatic lesions

Patients (n)

Cyst 9Abscess 2Haemangioma 7Focal fatty infiltration 9Focal nodular hyperplasia 2Resolving hepatitis 2Hypertrophic nodule 1Total 32

patients with focal liver lesions it is useful to differen-tiate a hepatocellular carcinoma from metastases andto make a determination of the primary site of thetumour. In our study a correct diagnosis was made byhistological examination in 93% of the cases; thisoverall accuracy is comparable with the results ofcytological examination'` but in contrast withcytology using histological examination there were

no false positives. Histological examination enablesnot only the differentiation between benign andmalignant focal lesions but also gives a more precise

tumour description"' and makes it possible to deter-mine the primary site of the tumour. In 15 patientswith proved hepatocellular carcinoma we noted one

advantage of the guided biopsy in that it enabled us

to yield histological evidence of hepatocellularcarcinoma. In this respect it is noteworthy that in sixcases where laparoscopies and conventional biopsieswere done, the diagnosis could not be verified bythese procedures. By using real time scan in theroutine and regular follow up of patients with chronicliver disease, either contour abnormalities or texturaltissue echo abnormalities can often be detected.

Ultrasonography does not always permit a definitediagnosis of malignancy or benignity, especiallywhen hepatoma develops on the underlying hetero-geneous pattern of cirrhosis. Serum AFP measure-ment has been the most frequently used screeningtest for the diagnosis of hepatocellular carcinomawith a diagnostic yield of 15-65% .. .'4 In our series ofpatients with proved hepatocellular carcinoma,raised serum concentrations of AFP were the firstclue to diagnosis in only 46% of the cases. Thiscomparatively low figure emphasises the need forultrasonically guided biopsies in patients withcirrhosis and textural tissue echo abnormalities. Inthese cases histology ensures the differentiationbetween primary and secondary malignant liverlesions. Using cytology alone, the diagnosis ofhepatocellular carcinoma is difficult - for example, inhepatitis or active cirrhosis cytology may showchanges mimicking hepatocellular carcinoma.' In thelast analysis histological examination is the onlymethod which can easily provide the diagnosis onwhich the choice of therapy depends.Haemangiomas are the most frequent benign

tumours of the liver and are present in 7% of thepopulation.` Characteristically in haemangiomasaspiration was followed by an immediate spurt ofblood and no specimen could subsequently beobtained in most of these cases. Whenever suchspurts of blood occurred the presence of haeman-gioma was suspected, a diagnostic advantage in thatconfirmation could easily be made by means of anAngio-computed tomography.'6 On ultrasoundexamination fat in the liver produces increasedechogenity. Focal fat is thus seen as an area ofincreased echogenity which makes it difficult for theclinician to differentiate between fat and malignantlesions.'7 In contrast, histologic examination of thebiopsies clearly showed an increased fatty infiltrationof the liver and no malignant cells. In individual casesthe interpretation of the histologic examination canalso be difficult, especially in patients with knownmalignant disease. In these cases a sampling error hasto be considered. In two patients guided fine needlebiopsies were therefore repeated, but in both casesthe same histologic result was revealed. The compari-son of fine needle biopsies from the focal lesion andfrom the normal appearing liver might provide oneway for a clearer diagnosis of focal fatty liver.A theoretical objection to fine needle biopsy is the

risk of causing widespread tumour cell dissemina-tion. The risk of tumour spread, however, is insignifi-cant when using the fine needle technique.' Althoughthe fine needle biopsy is considered safe it is nonethe-less imperative that bleeding be considered. In one ofour patients intra-abdominal bleeding did indeedoccur. Generally speaking it can be said that the

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complication rate of fine needle biopsy is low,'" andeven the possible angiomatous nature of hepaticlesions should not be considered an absolute contra-diction to biopsy.)

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