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Original Research |
1 Service de Radiologie, Hôpital Beaujon, Assistance Publique des
Hôpitaux de Paris, Université Paris, 100, Blvd. du
Général Leclerc, 92110 Clichy, France.
2 Service de Pathologie, Hôpital Beaujon, Assistance Publique des
Hôpitaux de Paris, Université Paris, Clichy, France.
Received May 11, 2007;
accepted after revision September 11, 2007.
Address correspondence to L. F. Pupulim
(law_dp{at}hotmail.com).
Abstract
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SUBJECTS AND METHODS. The study population included 472 consecutively registered patients with hepatic nodules who underwent sonographically guided fine-needle aspiration and core biopsies. During on-site cytologic analysis, the pathologist made a preliminary diagnosis of malignancy or negative for malignancy for each nodule. When a malignant lesion was diagnosed, immediate subtyping was attempted.
RESULTS. With immediate cytologic analysis, 280 (80.9%) of 346 malignant nodules were correctly identified without false-positive cases. With immediate subtyping, 113 (68.1%) of 166 cases of hepatocellular carcinoma, 28 (77.8%) of 36 cases of cholangiocarcinoma, and 113 (85.0%) of 133 cases of metastasis were detected.
CONCLUSION. High diagnostic accuracy for malignancy can be achieved with on-site cytologic evaluation of hepatic tumors. Specific diagnoses of hepatocellular carcinoma, cholangiocarcinoma, and metastasis also can be made on-site in most cases. The absence of false-positive diagnosis of malignancy at on-site cytologic examination may make additional biopsy unnecessary. We propose an algorithm for the cytohistopathologic management of hepatic tumors.
Keywords: core needle biopsy • fine-needle aspiration • immediate cytologic assessment • liver neoplasms
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The two methods of obtaining diagnostic material are fine-needle aspiration biopsy (FNA) and core needle biopsy. These two methods have similar results in the literature, and their combination has had the best results [6–11]. For some experts, FNA is more effective than core needle biopsy on the basis of cost, procedure-associated morbidity, and overall time to diagnosis [12, 13], although the results of this procedure are highly cytopathologist dependent. Furthermore, immediate cytologic assessment during FNA can be used to determine the adequacy of the sample and may increase the diagnostic sensitivity of the technique. Although immediate cytologic assessment was proposed in the 1980s [14, 15], few centers have adopted this technique as routine, and the diagnostic accuracy of on-site assessment has been described mostly in small and retrospective series [16–18]. The purposes of this study were to analyze prospectively with consecutive cases the diagnostic accuracy of immediate cytologic assessment in the detection of malignant hepatic lesions, to compare the results of immediate cytologic assessment with those of definitive cytologic examination, and to assess the performance of immediate cytologic assessment in the subtyping of malignant tumors.
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The study population included 472 adult patients. The 269 (57%) men and 203 (43%) women had a mean age of 58 years (range, 19–87 years). A total of 345 (73%) of the patients had one or two liver nodules, and 127 (27%) had multiple nodules. The mean size of the biopsied nodules was 3.9 ± 3.5 (SD) cm; median, 3 cm; range, 0.7–20 cm. All patients stayed in the hospital for at least 12–24 hours for postbiopsy observation, which is common practice at our institution. No major complications occurred.
FNA and Core Needle Biopsy Procedure
Four senior radiologists with more than 10 years of experience in abdominal
imaging performed liver biopsy at our institution. FNA and core needle biopsy
were always performed during the same session; FNA was performed first.
Patient sedation (10 mg of diazepam) was administered 1–2 hours before
the procedure. After induction of local anesthesia, the FNA samples were
obtained by an attending radiologist using a 22-gauge spinal needle (Spinocan,
Braun) or a 22-gauge Westcott biopsy needle under sonographic freehand
guidance (Sonoline Elegra sonography unit, Siemens Medical Solutions, or Aplio
sonography unit, Toshiba). Coaxial needles were not used. In patients with
multiple nodules, the most accessible nodule was targeted. After nodule
localization, the needle was introduced and passed gently through the lesion
without suction, and the samples were given to the cytopathologist. Direct
smears were prepared from part of the samples in the radiology department. Two
to 10 slides were prepared for each procedure depending on the amount of
material obtained. The cytopathologist decided whether material was adequate
after rapid microscopic evaluation. If not, FNA was repeated a maximum of
three times during the same session in an attempt to obtain an adequate
sample.
After spreading the aspirated material on slides, the cytopathologist prepared air-dried direct smears that were fixed on alcohol and prepared with eosin and Giemsa stains for immediate cytologic assessment. A number of slides were separated out for definitive cytologic analysis, and these slides were prepared in a different manner from the immediately evaluated slides. They were prepared in the pathology department with May-Grünwald and Giemsa stains after air-drying. Alcohol fixation was not used for these slides.
Immediately after the FNA procedure, core needle biopsy samples were obtained with an 18-gauge needle loaded into a semiautomatic biopsy system. Up to three core samples were obtained, and the adequacy of core needle biopsy was judged on the basis of the position of the needle in the target lesion and the size and color of the specimens. Biopsy of the tumor-free portion of the liver was performed on patients with chronic liver disease and when a diagnosis of benign tumor was suspected. After formalin fixation, the core needle biopsy samples were routinely processed and prepared with H and E, Masson trichrome, picrosirius red, Perls', and reticulin stains.
The number of passes for both FNA and core needle biopsy was recorded for each patient. All slides subjected to immediate and definitive cytologic assessment were analyzed by the same cytopathologist. The histologic analysis was performed by another pathologist. The interpretations were performed independently, and the findings were documented in separate reports.
Immediate Cytologic Diagnosis
On the basis of the results of rapid on-site FNA assessment in the
radiology department, the cytopathologist made a preliminary diagnosis of
malignant or negative for malignancy for each aspirated nodule. Doubtful cases
with no clear evidence of malignancy were considered negative for malignancy.
Cytologic features defining malignancy during rapid assessment were basically
the same as those used in the definitive cytologic analysis and included the
presence of high cellularity and marked cellular atypia. These features have
been well defined and extensively reported in the medical literature
[12,
19–23].
When a diagnosis of malignancy was made on site, the cytopathologist subtyped
the lesions as HCC, metastasis, or cholangiocarcinoma according to the
following specific features: HCC, presence of tridimensional cell groups,
basketing pattern (endothelial cells wrapped around groups of hepatocytes),
tumoral cells with prominent nucleoli and atypical naked hepatocytic nuclei;
metastasis, malignant pleomorphic cells in isolated or loosely cohesive groups
with or without an acinar pattern, rare traversing capillaries through cell
groups; cholangiocarcinoma, features of adenocarcinoma with tumoral round
cells arranged in a papillary or glandular pattern. The results of immediate
cytologic analysis were recorded to be compared with those of off-site
cytologic examination and with the definitive diagnosis.
Definitive Diagnosis
Sixty-four (13.5%) of the patients underwent surgical treatment, and the
definitive diagnosis was determined at histologic analysis of the surgical
specimen, which confirmed the core needle biopsy results in 46 cases. For the
other 18 patients, the decision for surgery was made even though core needle
biopsy results were inconclusive, because the cytologic results or follow-up
features indicated the need for surgery. For 366 (77.5%) of the patients,
biopsy analysis was used as standard of reference. The other 42 (8.9%)
patients had inconclusive histologic findings, and the tumors were not
resected. For these patients, the definitive diagnosis was based on imaging,
clinical, and biologic follow-up findings. Lack of tumor growth over 1–2
years defined a hepatic tumor as benign. Elevation of levels of serum tumor
markers and evidence of tumor growth on images or survey of metastatic lesions
during follow-up were used as criteria for defining a tumor as malignant.
Final diagnoses and the techniques of determination of the diagnoses are
summarized in Table 1.
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Statistical Analysis
The sensitivity, specificity, positive predictive value, and negative
predictive value of immediate and definitive cytologic examinations were
calculated as follows: sensitivity, division of the number of correct
diagnoses of malignancy by the number of proved malignant tumors and
multiplication of the quotient by 100; specificity, division of the total
number of correct diagnoses of benign tumor by the number of proved cases of
benign tumor and multiplication of the quotient by 100; positive predictive
value, division of the number of correct diagnoses of malignant cases by the
total number, correct and incorrect, of diagnoses of malignant tumor and
multiplication of the quotient by 100; negative predictive value, division of
the total number of correct diagnoses of benign cases by the total number,
correct and incorrect, of diagnoses of benign tumors and multiplication of the
quotient by 100.
The differences in proportion of diagnoses of malignancy in the two groups (immediate cytologic vs definitive cytologic) were compared. The differences were evaluated with the McNemar test because the groups included the same sample of subjects. Differences were considered significant at p < 0.05. All statistical analyses were performed with a statistical software package (StatView version 5.0, SAS Institute).
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Immediate Cytologic Diagnosis of Malignancy
A correct diagnosis of malignancy was made at immediate cytologic
assessment for 280 (81.0%) of the 346 patients with malignant disease. The
overall results of the immediate and definitive cytologic examinations are
summarized in Table 2. There
was no statistical difference in the sensitivity or specificity of the two
procedures for the diagnosis of malignancy. Nevertheless, 11 (2.3%) more cases
of malignant tumors were detected at definitive cytologic examination than at
on-site assessment; this difference was significant according to the McNemar
test.
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Immediate Cytologic Subtyping
Subtyping was correct in 254 (90.7%) of the 280 cases diagnosed as
malignant on-site. Immediate cytologic diagnosis of malignant subtypes was
correct in 113 (68.0%) of 166 cases of HCC, 113 (85.0%) of 133 cases of
metastasis, and 28 (77.8%) of 36 cases of cholangiocarcinoma. There were no
false-positive diagnoses of cholangiocarcinoma, two false-positive diagnoses
of HCC (one cholangiocarcinoma, one metastatic lesion), and six false-positive
diagnoses of metastasis (six cholangiocarcinomas). In all of these
false-positive cases, the final diagnosis was another malignant tumor, and in
all cases of false-positive diagnosis of metastasis, there was no suspected
primary site at the time of biopsy.
Algorithm
An algorithm for the cytohistopathologic management of hepatic tumors was
developed on the basis of the results of this study
(Fig. 1). The absence of
false-positive diagnosis of malignancy at on-site cytologic examination
suggests that in well-defined cases, the additional core biopsy procedure is
unnecessary, especially for cholangiocarcinoma and metastatic lesions with
known primary sites. Use of this algorithm would have allowed 120 (25%) of the
patients in this study to avoid additional biopsy (28 patients with
cholangiocarcinoma, 92 patients with hepatic metastasis and known primary
cancer site).
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Although FNA is often performed for hepatic tumors, on-site cytologic evaluation is not generally performed at most centers, and published results on this approach are limited [24]. On-site evaluation of hepatic nodules with FNA is often performed only to determine the adequacy of material obtained but not to discern an immediate diagnosis [15, 25]. As in most published reports [26–28], the specificity in our series reached 100% because only tumors that had clear evidence of a malignant pattern were classified in the malignant group.
To our knowledge, few studies have been conducted to evaluate on-site cytologic diagnosis of hepatic lesions. In a series of evaluations of various sites, Silverman et al. [18] found a sensitivity of 96% and a specificity of 100% for immediate cytologic FNA diagnosis of malignancy in 31 patients with hepatic lesions. Stewart et al. [16] also emphasized the importance of rapid assessment of cytologic preparations. In that series of 141 patients with abdominal lesions (105 with hepatic lesions), a provisional diagnosis was made during the procedure for 103 (73%) FNA specimens (92 malignant cases, 11 reactive or inflammatory lesions). The sensitivity of immediate cytologic evaluation in the diagnosis of malignancy was 71.3%. In that experience, there was no significant difference between provisional and final cytologic diagnoses.
We found that on-site cytologic assessment can be used for accurate diagnosis of the main subtypes of malignant hepatic tumors with a sensitivity of 68% for HCC, 78% for cholangiocarcinoma, and 85% for metastasis. These results confirm those of a study in which the investigators [29] found good performance of immediate cytologic assessment of hepatic tumors with correct subtyping of 71% of lesions. To our knowledge, the diagnosis of cholangiocarcinoma with on-site cytologic assessment has not been studied. Not surprisingly, as with conventional cytologic examination, the diagnosis of HCC with immediate assessment was more difficult than that of metastasis, especially for well-differentiated HCC [30–32].
We propose a diagnostic algorithm based on the results of on-site cytologic evaluation (Fig. 1). For instance, patients with a diagnosis of metastasis at immediate cytologic assessment and a known extrahepatic site of primary cancer can avoid further biopsy. In contrast, when the primary site is unknown, biopsy is warranted, especially to obtain additional morphologic and phenotypical features of the malignant proliferation. For primary hepatic cancer, cytologic diagnosis of cholangiocarcinoma appears to be reliable. There were no false-positive cases in our series, so additional core needle biopsy could have been avoided. Finally, in cases of HCC, we still recommend core needle biopsy to evaluate additional prognostic histopathologic features of the tumor (especially the grade of differentiation), although treatment strategies such as radiofrequency ablation can be initiated immediately after diagnosis with immediate cytologic assessment. The proposed algorithm may have an important effect on the cytohistopathologic management of hepatic tumors. In our series, use of the algorithm would have avoided additional core needle biopsy on 25% of patients.
Our study had limitations. First, both immediate and definitive cytologic evaluations were performed by the same cytopathologist. Therefore the definitive cytologic diagnostic accuracy was probably related to or influenced by the immediate assessment, especially when malignancy was diagnosed during the on-site evaluation. Second, only one cytopathologist prospectively interpreted all the findings. We acknowledge that diagnostic accuracy is related to the experience of the cytopathologist, and we did not evaluate interobserver variability. On the other hand, cytologic diagnosis, which can be considered an art, is based on well-defined cytologic features that have been extensively described in the medical literature [12, 19–23]. Third, core needle biopsy results were used to determine the definitive diagnosis in a great number of cases, as in most published series. Therefore, we did not compare on-site cytologic results with those from core needle biopsy because such a comparison has inherent bias.
Results of some studies have suggested that the caliber of the needles [13, 26] and the small number of passes needed to obtain adequate material [7, 33] may be responsible for the lower rate of complications of FNA compared with core needle biopsy. Thus we can hypothesize that optimization of this technique during the procedure with on-site cytologic evaluation may decrease the risk of complications. Another useful technique for percutaneous biopsy of the liver is the coaxial needle system. In this technique, a needle introducer remains in position while multiple needle passes are made. The technique has been shown [34] to prevent tumor seeding in the needle track. In small tumors, however, adequate needle positioning with coaxial technique can be challenging [35]. The assistance of a pathologist in the radiology department is time-consuming [36], but it may be useful for reducing the number of repeated procedures. Cost-effectiveness, which is another important issue, was beyond the scope of our study.
This study showed that at FNA of hepatic tumors, immediate cytologic assessment by a pathologist in the radiology department has high accuracy in the diagnosis of malignancy and can be used to assess tumor subtype in most cases. This practice not only increases diagnostic yield but also may prevent core biopsy procedures on selected patients. We recommend that a pathologist routinely perform on-site evaluation of FNA specimens of hepatic tumors.
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