Sazetak Vizuelno vodjena aspiracija promena u jetri finom iglom je postala standardni dijagnosticki metod za razlikovanje malignih od benignih promena. Medjutim, primena ove metode predstavlja problem u sredinama gde postoji nedostatak modernih imedzing tehnika. Cilj ovog prospektivnog ispitivanja je da se odredi znacaj vizuelno nevodjene, direktne aspiracione punkcije finom iglom i to promena cije je postojanje prethodno bilo potvrdjeno primenom radioaktivnog tehnecijuma, ultrazvukom i/ili kompjuterizovanom tomografijom. Na osnovu histoloskog,, citoloskog, i klinickog nalaza krajnja dijagnoza je postavljena u 107 bolesnika od kojih je 52 imalo maligne, a 55 benigne promene u jetri. Medju pacijentima sa malignitetima, citoloskim pregledom je posumnjano na malignost u 1 slucaju. Definitivna dijagnoza maligniteta je postavljena u 41 bolesnika. Medjutim u 10 pacijenata maligna promena je ovom metodom ostala neutvrdjena. Medju bolesnicima sa benignim promenama u jetri citoloski nalaz je u svih potvrdio benignu prirodu. Ukupna sezitivnost, specificnost, pozitivni i negativni prognosticka vrednost primenjene metode je bila 81,100, i 85%. Komplikacije vezane za primenu ove metode nisu bile registrovane.
Zakljuceno je da aspiracija promena u jetri finom iglom jednostavna i bezbedna dijagnosticka metoda kojom mogu da se ispituju promene u jetri posebno u uslovima kada nedostaje moderna dijagnosticka oprema.
Kljucne reci: citoloska dijagnostika, aspiracija finom iglom, FNA, promene u jetri, metastaze, primarni malignitet
Introduction Fine needle aspiration (FNA) of liver changes in diagnosing hepatocellular carcinoma and liver metastases has proven to be a safe, sensitive, and specific method when guided by ultrasound (US) or computed tomography (CT) ( 1-11 ). Numerous studies have reported a sensitivity between 67% and 100% (12-28). However, its value remains to be determined in geographic areas where the availability of high-tech equipment is in a lack. The aim of this communication is to present our experience with direct FNA in diagnosing primary malignant and/or metastatic liver disease in patients with palpable and nonpalpable hepatic changes, and to compare with already reported results with imaging-guided FNA. To date, a large prospective evaluation of the accuracy of direct FNA or the safety of the technique has not been reported yet. Our preliminary results have encouraged us to use blind FNA as the initial diagnostic tool in the majority of patients with hepatomegaly caused by suspected of r astablished malignant liver disease (MLD). PATHIENTS AND METHODS From 1991 until 1996 we prospectively studied the accuracy of nonguided (direct) FNA of liver lesions in 107 consecutive non-selected patients in the Department of Internal Medicine C at Rambam Medical Center. The aspirations were performed either to confirm or exclude suspected primary or metastatic liver malignancy based on clinical findings in symptomatic patients and prior to any imaging exploration of the liver. In a small number of cases, results of radioisotope, US or CT scan were present. All patients signed informed consent prior to aspiration and the study protocol confirmed to the ethical guidelines of the Declaration of Helsinki as reflected in a priori approval by the hospital’s Human Research Committee. Aspirations were performed in some patients who were scheduled for abdominal surgery for malignant and non-malignant lesions but not suspected of having MLD. Informed consent was obtained from each patient prior to the surgery. Technique Specimens for cytologic examination were obtained by direct insertion of a 22-gauge needle (0.8 ´ 80 mm). Aspirated biopsy tissue was approximately 0.2-0.3 mm in diameter, and 2-3 mm in length. All aspirations were performed by the same physician, and the penetrating sites of the liver were subcostal or transcostal. An attendant cytopathologist was present in all cases to verify that adequate numbers of cells of the expected type were present in the sample. In 93 patients direct FNA was performed from both the right and left sides of the liver, in 13 patients only from the right side and in 1 patient only from the left side of the liver. In cases of palpable liver mass or hepatomegaly possibly caused by liver malignancy, but without any palpable mass, the aspiration was usually performed prior to any imaging exploration of the liver. In cases of unifocal or multifocal lesion(s) demonstrated by imaging methods (with or without an enlarged liver), the puncture sites and directions of the needles were blindly directed towards the estimated site of the lesion. In each FNA procedure, 3 to 5 aspirations from different insertion points were made, with 6 to 8 needle passes for each aspiration. Contraindications for FNA included history of marked hemorrhagic tendency, a high increase in D-dimers (>0.5 units), reduced platelet count (50,000 platelets/mm3), or prolonged prothrombin (>13 sec, inr >1.5) or partial thromboplastin time (>36 sec.). The aspirate was expelled onto glass slides, smeared and fixed with 95% ethyl alcohol, and later stained by Papanicolaou's method. One slide was air-dried for May-Grünwald/Giemsa staining. Cytopathologic interpretation The experienced cytopathologist, Dr. E. Marberger, interpreted the cytologic findings. These were reported as follows: 1) acellular, 2) unsatisfactory, 3) no malignancy, 4) atypical-reactive, 5) malignancy cannot be ruled out (inconclusive), 6) suspected malignancy and 7) definite malignancy. Whenever possible, the tumor cell type was specified. Clinical, laboratory, radiologic, imaging, operative, histologic and cytologic data were compiled for each patient. Follow-up information was obtained in order to reach a final diagnosis and to evaluate the diagnostic role played by FNA. Data were obtained by reviewing Rambam Medical Center charts, the discharge summaries of other hospitals and telephone communication. Statistical analysis To determine the sensitivity and specificity of cytologic diagnoses, it was necessary to classify cytologic findings for each patient as either malignant or benign. For this purpose, patients with cytologic findings of ‘no malignancy’ and ‘atypical-reactive’ were classified as having benign cytologic diagnoses, while patients with cytologic findings in liver aspirations from the right or left side of ‘suspected’ and ‘definite malignancy’ were diagnosed as having malignancy. The cytologic findings of FNA were categorized as true-positive, true-negative, false-positive and false-negative. The accuracy of true and false cytologic diagnoses was verified against histologic, cytologic and clinical categories. A cytologic diagnosis was defined as true-positive if a patient with malignant cytologic diagnosis had one or more of the following: 1) Histologic findings of malignancy based either on liver tissue obtained by liver needle biopsy, surgery or autopsy or on histologic findings of malignancy from another site revealing malignant cells similar to those obtained by FNA of the liver. 2) Cytologic findings of malignant cells from other organs or from body fluids exhibiting malignant cells similar to those obtained by FNA of the liver. 3) A combination of the following clinical findings: palpable liver mass, hepatomegaly or elevated serum alkaline phosphotase; imaging scan of the liver suggesting malignancy; steady deterioration, with survival time not exceeding 12 months, with or without indication of MLD on death certificate. A cytologic diagnosis was defined as true-negative if patients with negative cytologic diagnosis also had benign histologic diagnosis of liver biopsy or no evidence for MLD during surgery and/or his subsequent clinical course was considered characteristic of a benign disease (improvement, either spontaneously or following therapy). Specificity was determined by dividing true-negatives by the number of lesions ultimately found to be benign. RESULTS Based on histologic, cytologic and clinical findings, final diagnoses were accurately made in 107 patients, of whom 52 (49%) had malignant and 55 (51%) benign liver disease (BLD). Sixteen patients (15.0%) had a history of prior malignancy. Table 1. All patients underwent at least 1 of the following liver imaging explorations: technetium-99m scanning, US or CT. In some patients imaging studies were negative. Among 55 patients with BLD, imaging scans suggested malignancy in 9 (16%) patients. Of these, 3 patients presented with multifocal lesions and 6 with unifocal lesions. The final diagnoses of the patients with multifocal lesions were liver cirrhosis in 2 patients and liver abscess in 1. Final diagnoses of patients with unifocal lesions were liver cirrhosis in (3 patients), liver abscess (2 patients) and pseudoinflammatory liver tumor (1 patient). The final diagnoses of 55 patients with BLD included extraliver malignancy (27 patients), cholelithiasis (8 patients), liver cirrhosis (7 patients), villous adenoma (4 patients), liver abscess (4 patients) and miscellaneous (5 patients). Among 52 patients with MLD, histologic findings verified the cytologic diagnosis of malignancy in 31 patients (60%). In 5 patients (10%) cytologic diagnosis of malignancy was verified by matching with cytologic tumor cells obtained from other organs or from body fluids, and in 16 patients (31%) by clinical findings alone. Imaging scans suggested malignant multifocal lesions in 79% of these patients and unifocal lesions in only 21%. The cytologic findings indicated suspected malignancy in 1 patient and suggested definite malignancy in 41 patients, but failed to disclose malignancy in 10 patients (Table 2). Among the 52 MLD patients, malignant cytological findings were obtained in 42/51 (82%) aspirations performed from the right side of the liver, in 24/44 (50%) aspirations performed from the left side of the liver and in 19/43 (44%) aspirations performed from both sides of the liver. The malignant cytological findings included hepatocellular carcinoma in 4 patients, liver metastases in 37 patients and adenocarcinoma in 21 patients. Other cytologic diagnoses included unspecified carcinoma (6 patients), small cell carcinoma (2 patients) and cholangiocarcinoma, transitional cell carcinoma and malignant lymphoma (1 patient each). In the 52 MLD patients, 89 liver scans suggested malignancy, of which 46 were malignant multifocal lesions and 23 (26%) malignant unifocal lesions. Table 3 shows the relationship between direct FNA cytodiagnosis in patients with MLD and type of suspected malignant liver lesion detected by various kinds of liver imaging scanning. The proportion of true-positive cytologic diagnoses among patients with liver scans suggesting multifocal lesions was 80% (39/49), while 65% (15/23) indicated unifocal lesions. Using the defined histologic, cytologic and clinical criteria for MLD and BLD, the sensitivity of FNA cytology for the diagnosis of malignancy was 81%, while the specificity and positive and negative predictive values were 100, 100 and 85%, respectively. The overall diagnostic accuracy rate of FNA cytology was 91%. The final malignant diagnoses of the 52 patients with MLD included adenocarcinoma with various differentiation (26 patients), carcinoma of unknown origin (7 patients), hepatocellular carcinoma (4 patients), small cell carcinoma (2 patients) and malignant lymphoma, transitional cell carcinoma and cholangiocarcinoma (1 patient each). No major complication attributable to the procedure was observed except 1 case with pneumothorax. Pain and tenderness at the puncture site was not an infrequent complaint. The median survival of 46 patients with MLD was 1 month (range, 1-36 months), whereas the median survival of 23 patients with BLD was 15 months (range, 1-55 months). DISCUSSION FNA is a well-established method for cytodiagnosis of primary liver cancer and liver metastases. In cases of benign lesions it may suggest the diagnosis of an abscess or a hemangioma. FNA of the liver guided by US or CT has proven to be a safe and accurate method for diagnosing hepatocellular carcinoma (1-8) and liver metastases ( 1- 11). Nevertheless, nondetection of pathologic findings by imaging liver scans does not preclude the presence of malignancy. Heiken et al prospectively evaluated the ability of CT to detect malignant lesions in 8 patients who subsequently underwent hepatic lobectomy or transplantation ( 30 ). Among 37 malignant lesions demonstrated by pathologic evaluation, only 14 (38%) were detected by contrast-enhanced CT, but no lesions smaller than 1 cm in diameter (n=18) were detected by the CT. We therefore suggest that actual malignancy is more frequent than its on-screen appearance. The most important requirement for cytodiagnosis of liver lesion is a representative sample. Cytopathologic techniques permit the identification of malignancy in liver aspirate exept in well-differentiated hepatocellular carcinomas where tissue biopsy is preferred. The reported sensitivity of US- and CT-guided FNA ranges between 67% and 100% (12-28). In the present study, the sensitivity, specificity, and positive and negative predictive values of direct FNA for cytodiagnosis of liver lesions were 81, 100, 100 and 85%, respectively. The overall accuracy rate was 91%. These data indicate that the diagnostic accuracy of direct FNA of liver lesions may be similar to imaging-guided FNA. Tissue sampling by direct FNA representing a larger liver volume was accomplished by a number of aspirations in various directions (multiple insertion points) and by multiple (6 to 8) long passes in each aspiration. Direct sampling by aspiration of palpable liver masses in patients with malignant cytological findings and palpable liver mass was performed (21% of patients (n=9 of 42). Included in sampling by direct FNA were 89 patients with liver scans suggesting malignancy and with large areas of the liver being affected as determined by imaging scannings. Scannings suggesting malignant multifocal lesions (n=49 of 89, 55%) were more prevalent than those indicative of unifocal lesions (n=23 of 89, 26%). Histopathologic examination of patients with rectal carcinoma showed that the depth and distance involvement of the tumor exceeds the macroscopically or radiologically defined tumor border because of an infiltrative growth pattern (31-33). Consequently, although the aspirating needle does not necessarily aspirate the actual imaged lesion, it certainly does aspirate some surrounding malignant cells. This argument may be supported by the facts that 65% of patients with MLD had hepatomegaly which could only be attributed to malignancy and that the rate of malignant cytologic findings in patients with unifocal malignant liver lesion was only slightly less than that of patients with multifocal lesions (65% vs 79.0%) (34). The present study was conducted in order to establish the cytologic examination as a reliable diagnostic method. Twelve of 107 patients with palpable lesions were included for statisical study analysis. Evaluation of the diagnostic accuracy of our cytologic findings was carried out on 3 levels. In 31 of the 52 patients with MLD (60%), cytologic diagnosis was verified either by histologic findings obtained by liver needle biopsy, at surgery, at autopsy or by histologic findings of malignancy from another site revealing malignant cells similar to those obtained by FNA of the liver. This constituted the highest level of verification. The cytologic diagnosis of malignancy was verified in 35 patients by matching with cytologic tumor cells obtained from other organs or from body fluids, and in 74 patients by clinical findings alone. The defined clinical findings suggesting malignancy were observed in only 2 of 94 patients with BLD (2%) with corresponding cytologic findings. In these 2 patients the survival time <12 months was due to cardiovascular events. The validity of the cytologic findings is also supported by the survival time. The median survival for patients in whom the cytologically diagnosed MLD was verified against histologic, cytologic and clinical findings was 2, 3 and 2 months, respectively. There were 10 patients (19%) with false-negative cytologic findings, due to failure to obtain a representative malignant sample rather than to misinterpretation of the smears. It has been shown that superficial nonrepresentative FNA of a malignant tumor may reveal only necrotic material, degenerative changes or inflammatory reactions, which are frequently observed but do not reveal the presence of an underlying tumor (19). In order to lower the rate of false-negative cytologic findings, we suggest that FNA be repeated in patients clinically suspected of having malignancy despite negative cytologic findings. Negative cytologic findings must be acepted with caution because of significant false-negative rate. However, because a malignant cytologic diagnosis is considered to be equivalent to a malignant histologic diagnosis, high specificity is a necessary requirement. In our series no false-positive cytologic diagnosis was reported. False-positive cytologic diagnoses have been reported in the literature, ranging from 4% to 20% (9,13,19,20). No major complication attributable to the procedure was observed, while pain, tenderness and local skin hemorrhage at the puncture site were not infrequent. Since direct FNA yields similar results and has the capacity for early detection of abnormal cells, this method is simple for cytodiagnosis of liver malignancy, particularly in areas where the availability of technological equipment is limited. Limitations of this study is that this report do not imply any alternative in replacing the current practice of US guided needle biopsy, nor does obviate other available and useful methods, particularly in diagnosing localized liver changes when the level of medical technology permit. Blind FNA may be useful when imaging-guided FNA is not available and the tumour is palpable, large or diffuse. It is still difficult for nonguided (direct and blind) FNA of palpable and nonpalpable liver lesions to classify tumours and to make differential diagnosis of atypical proliferation of liver cells and well differentiated hepatocellular carcinoma. We suggest that a controlled study of blind versus non-blind FNA as well as analysis of tumor type be conducted.
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