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Keywords:

  • false-negative;
  • endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the pancreas;
  • cystic lesion;
  • solid lesion;
  • pancreatic resection

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

The diagnosis of pancreatic tumors is often complicated because of sampling and interpretive challenges. The current study was performed to determine the rates, types, and causes of diagnostic discrepancies.

METHODS

The authors retrospectively reviewed cytology cases from 2004 to 2010 using matched surgical resection cases as the gold standard.

RESULTS

A total of 733 cases were divided into 3 categories: 1) positive or suspicious (290 cases); 2) negative or atypical (403 cases); and 3) unsatisfactory (40 cases). Of these cases, 101 fine-needle aspiration (FNA) cases had matched surgical resections including 58 positive diagnoses, 39 negative diagnoses, and 4 unsatisfactory diagnoses. All 19 discrepant cases represented false-negative diagnoses without any false-positive cases noted, which included 2 cases with interpretive errors (10%) and 17 cases with sampling errors (90%). All matched cytology cases were divided into 5 subgroups based on the type of lesion or type of error and were analyzed for sensitivity and specificity. The sampling error rate in cystic lesions (8 of 24; 33%) was significantly higher than that in solid lesions (9 of 73; 12%). The false-negative rate in the interpretive error group (3%) was significantly lower than that in the sampling error group (23%).

CONCLUSIONS

The results of the current study confirm that pancreatic endoscopic ultrasound-guided FNA diagnosis has a very low false-positive rate but a relatively high false-negative rate using matched surgical resections as the gold standard. The major cause of a false-negative cytology diagnosis is sampling error and the rate of sampling error in cystic lesions is significantly higher than that in solid lesions. Cancer (Cancer Cytopathol) 2013;121:449-58. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Pancreatic cancer is the fourth leading cause of cancer death in the United States.[1] The very high mortality rate is the result of late presentation of most patients, a high morbidity associated with pancreatic surgical resection, and a lack of other effective treatment options. The majority of pancreatic masses are ductal adenocarcinomas.[2] However, nonneoplastic entities including primarily chronic pancreatitis and its sequelae, especially autoimmune pancreatitis, can demonstrate overlap with pancreatic neoplasms with regard to both imaging characteristics and pathologic diagnosis, creating a diagnostic challenge from both a clinical and pathologic standpoint. Cystic neoplasms also arise in the pancreas including mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN) with or without associated invasive carcinoma, serous cystadenoma, and solid pseudopapillary neoplasm. These cystic neoplasms, along with nonneoplastic entities, carry various prognoses and also have different associated treatment options, thereby making the correct diagnosis extremely important for both prognosis and management decisions.

Endoscopic ultrasound (EUS) has become one of the preferred imaging techniques in evaluating pancreatic lesions and has high sensitivity as well as the ability to perform staging and tissue sampling at the time of the procedure.[3-5] In fact, primary diagnosis of the majority of pancreatic tumors is now based on EUS-guided fine-needle aspiration (EUS-FNA) biopsy and bile duct brushing. Cytologic diagnosis has reduced patient morbidity and needle tract seeding compared with computed tomography (CT) or ultrasound-guided core needle biopsy. In addition, EUS-FNA had demonstrated high diagnostic accuracy for the majority of pancreatic solid lesions[6-8] and has added value to imaging alone for cystic lesions.[9] A generally accepted false-positive rate for an EUS-FNA diagnosis of gastrointestinal lesions is 0% to 1%.[8, 10-15] These studies predominantly used both clinical follow-up information and surgical resection as the gold standard, with too few resected specimens for confirmation and without regard to the use of neoadjuvant therapy.[12, 14] However, this has been recently challenged by 2 studies.[12, 15] Using the surgical resection as a gold standard and including cases with a diagnosis of “suspicious for malignancy” in the positive group, the false-positive rate was 2.2% and 3.8%, respectively.[12, 15]

The diagnosis of malignancy in cystic lesions is often complicated because of sampling difficulty and reactive changes associated with significant inflammation and atypia. In addition, dysplastic lesions can arise in the pancreatic ductal system or in an underlying mucinous neoplasm and can be confused with malignancy depending on the degree of cytologic atypia.[6, 13, 16, 17] Both false-positive and false-negative diagnoses lead to significant consequences for clinical management[18] because a positive diagnosis often leads to major surgery (pancreatectomy) or radiotherapy/chemotherapy and a false-negative diagnosis delays patient treatment and may result in the loss of surgical resectability.

Cytologic diagnosis with EUS-FNA has been studied extensively, with widely varying sensitivity.[19-24] The sensitivity has been reported to range from 14% to 100%, whereas specificity has ranged from 69% to 100%.[13, 21, 23, 25, 26] However, as mentioned, only rare studies have used the surgical resection as the gold standard to evaluate the cytopathologic diagnostic error and clinical sampling error separately for the diagnosis of pancreatic cystic and solid lesions. In the current study, we reviewed our pancreatic cytology cases with matched surgical specimens for a period of 6 years. The objective was to evaluate both cytopathologic diagnosis and clinical sampling error for both solid and cystic pancreatic lesions with EUS-FNA.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Design

The current study was a retrospective study of all pancreatic surgical resections performed in patients with prior EUS-FNA from 2004 to 2010 and identified through a review of the pathologic database at the University of Rochester Medical Center. A total of 733 pancreatic EUS-FNA biopsy cases, including solid and cystic lesions, were identified. A total of 264 pancreatic surgical resections were performed at the study institution during the same time period, 101 of which had a prior FNA diagnosis in our files. Some patients with typical symptoms and a resectable pancreatic mass noted on CT scan underwent surgery without EUS-FNA. A total of 101 matched cases were used for our analyses (56 women and 45 men with a mean age of 57 years [range, 34 years-88 years]). All EUS-FNA cytological slides from matched cases were independently reviewed, in a blinded manner, by 3 cytopathologists (K.W., T.B., and Z.Z.), one of whom cospecialized in gastrointestinal pathology (Z.Z.). All surgical histologic slides from matched cases were reviewed by this individual. All original diagnoses from our database were reviewed and cases with discordant diagnoses between the original cytologic diagnosis and surgical resection diagnosis were identified. Using the surgical pathology resection diagnosis as the gold standard, the number of false-positive, false-negative, true-positive, and true-negative cases was determined.

This study was approved by the Research Subjects Review Board of the University of Rochester (RSRB00044788).

Definition of True-Positive, True-Negative, False-Positive, and False-Negative Cases

Based on the review of matched EUS-FNA and surgical resection cases, we determined the true-positive, true-negative, false-positive, and false-negative cases as defined below. False-positive cases were defined as those with an original FNA diagnosis of “positive or suspicious for malignancy or neoplasm,” that were proven to be benign based on review of the surgical specimen. False-negative cases were defined as those with an original FNA diagnosis of “atypical or negative for malignancy” that were proven to be adenocarcinoma, pancreatic endocrine neoplasm, or other solid tumors or intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), or mucinous cystic neoplasm with associated invasive adenocarcinoma (MCNA) on the surgical resections. True-positive cases included an original FNA diagnoses of “positive or suspicious for malignancy or neoplasm,” that were found to be adenocarcinoma, pancreatic endocrine neoplasm, or other solid tumors or IPMN, MCN, or MCNA on the surgical resection. True-negative cases included original FNA diagnoses of “atypical or negative for malignancy or neoplasm,” that were found to be negative for solid tumor or neoplasm and negative for IPMN, MCN, or MCNA on the surgical resection. Discrepant cases were rereviewed further as a group for consensus by 3 pathologists. A reason for discrepancy was established based on the consensus diagnosis. Sampling error (SE) was defined as the absence of sufficient material for definite diagnosis within the submitted cellular sample, and was usually due to difficulties related to sampling the lesion by the gastroenterologist. Interpretive error (IE) was defined as a diagnostic error resulting from the cytopathologist's misinterpretation or failure to identify malignant cells that were present.

In addition, the cytologic specimens that contained only contaminating gastrointestinal tract epithelial cells and/or blood in both solid or cystic lesions or rare benign pancreatic cells in solid lesions were defined as “nondiagnostic” and were removed from the current analysis.

Subgroups of Pancreatic FNA Cases by SE, IE, Cystic Lesions, and Solid Lesions

In the current study, the matched EUS-FNA cases included both cystic and solid lesions. In addition, the false-negative cases also included both SEs and IEs. First, we combined all matched EUS-FNA cases together, including both SE and IE cases, as group 1. To compare the influence of SE and IE on the false-negative rate and other parameters, we divided the false-negative diagnosis cases into an IE-only group (group 2) and an SE-only group (group 3). Pancreatic cystic tumors are very difficult to sample adequately and therefore a definite diagnosis is made using EUS-FNA, but the solid tumors are relatively easier to sample. Therefore, we separated cystic and solid lesions into groups 4 and 5 to compare them. True-positive and true-negative and false-positive and false-negative cases are listed in Tables 1 and 2. All 5 groups were defined further as follows. Group 1 was comprised of SE and IE cases among all cystic and solid lesions. In this group, the false-negative rate included all cases with both SEs and IEs. Group 2 was comprised of IEs alone in all cases; cases with SEs were removed from the analysis. Group 3 was comprised of SEs alone in all cases. Group 4 was comprised of SEs alone in cystic lesions. In this group, analysis focused on the false-negative rate for sampling cystic lesions. Group 5 was comprised of SEs alone in solid lesions. In this group, the analysis focused on the SE of solid lesions only. The sensitivity, specificity, positive predictive value, and negative predictive value; false-positive and false-negative rates; and accuracy were also calculated in all 5 groups. False-negative rates, sensitivity, and accuracy in various groups were compared.

Table 1. FP and FN Cases and TP and TN Cases in Cystic and Solid Lesions of Matched FNA Cases
ResultCystic LesionSolid LesionTotal
  1. Abbreviation: FN, false-negative; FNA, fine-needle aspiration; FP, false-positive; TN, true-negative; TP, true-positive.

  2. a

    These 11 cases include 9 sampling errors and 2 interpretative errors.

FN811a19
FP000
TP75158
TN91120
Insufficient224
Total2675101
Table 2. Subgroups of Pancreatic EUS-FNA Cases With or Without Sampling Errora
SubgroupSE and/or IETPTNFPFNTotal
  1. Abbreviations: CL, cystic lesion; EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; FN, false-negative; FP, false-positive; IE, interpretative error; SE, sampling error; SL, solid lesion; TN, true-negative; TP, true-positive.

  2. a

    Includes 1) SE and IE in all cases including CL and SL; 2) IE in all cases including CL and SL; 3) SE in all cases including CL and SL; 4) SE in CL; and 5) SE in SL.

1SE and IE in all cases582001997
2IE only in all cases58200280
3SE only in all cases582001795
4SE in CL790824
5SE in SL51110971

Studies of sensitivity, specificity, and other parameters of pancreatic EUS-FNA were challenged by the lack of clinical follow-up and a gold standard with which to prove true-negative and false-negative EUS-FNA cases. In the current study, the false-negative cases were based on matched resection specimens, but there were 403 total negative pancreatic EUS-FNA cases during this period at the study institution. Only 39 cases were resected, including 19 cases proven to be false-negative results and 20 true-negative cases by comparing the surgical resection diagnosis. The remaining cases were unknown because the majority of negative cases did not undergo surgical resection or have available clinical follow-up. Therefore, the sensitivity, specificity, and other parameters in the current study are conditioned because of the limited number of matched cases. However, we studied all matched cases from 2004 through 2010, which may be representative of the general distribution of EUS-FNA samples.

Statistical Analysis

We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy from matched EUS-FNA cases in 5 categories, and the associated 95% confidence intervals with exact binomial confidence limits (95% CIs). The proportion test was used to address whether the rates in 2 different categories were significantly different. Significance for comparing results was defined as P < .05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Diagnostic Discordance Between Pancreatic EUS-FNA Cytology and Matched Surgical Resections

A total of 733 pancreatic EUS-FNA biopsy cases, including solid and cystic lesions, were identified by reviewing the pathology database at the University of Rochester Medical Center from 2004 to 2010. These 733 FNA cases were divided into 3 categories: positive or suspicious, negative or atypical, and unsatisfactory. A total of 264 pancreatic surgical resections were performed at the study institution during the same time period, 101 of which had a prior FNA diagnosis in our files. The 101 FNA cases included 58 positive diagnoses, 39 negative diagnoses, and 4 unsatisfactory diagnoses (Table 3). The surgical resection diagnoses of these 101 cases included adenocarcinoma, pancreatic endocrine neoplasm, and solid pseudopapillary neoplasm, among others (Fig. 1) (Table 3). All slides from matched EUS-FNA specimens were reviewed by 3 cytopathologists independently. Comparing the original cytologic diagnosis with the matched histologic diagnosis, 19 (19%) discordant cases were identified among 97 adequate EUS-FNA cases (Table 4). Based on the definition from the previous description, 58 cases were designated as true-positive results, 20 cases as true-negative results, 19 cases as false-negative results, and no cases were designated as false-positive results (Table 1).

Table 3. FNA Diagnoses in Cases With Matched Pancreatic Resections From 2004 Through 2010
DiagnosisACGISTPENSUSATYNEGUNSATTotal
  1. Abbreviations: AC, adenocarcinoma, ATY, atypical; FNA, fine-needle aspiration; GIST, gastrointestinal stromal tumor; NEG, negative; PEN, pancreatic endocrine neoplasm; SUS, suspicious; UNSAT, unsatisfactory.

No. of FNAs322121211284101
image

Figure 1. Examples of paired endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and surgical resection (SR) cases are shown. (A) An FNA of ductal adenocarcinoma is shown (Papanicolaou stain, × 400). (B) SR of a ductal adenocarcinoma is shown (H & E, × 200). (C) An FNA of a pancreatic endocrine neoplasm is shown (Diff-Quik stain, × 200). (D) SR of a pancreatic endocrine neoplasm is shown (H & E, × 400). (E) An FNA of a solid pseudopapillary neoplasm is shown (Papanicolaou stain, × 400). (F) SR of a solid pseudopapillary neoplasm is shown (H & E, × 400).

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Table 4. Clinical and Pathologic Data From All Discordant Cases Between Surgical Resection Specimens and EUS-FNA Cytology Specimens
Case No.Age, YearsSexTumor LocationTumor Size, cmSurgical Resection DiagnosisCategoryCytology DiagnosisDifferentiation
  1. Abbreviations: AC, adenocarcinoma; EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; IE, interpretive error; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; MCNA, mucinous cystic neoplasm with associated invasive carcinoma; PEN, pancreatic endocrine neoplasm.

165ManHead2.4IPMNCysticNegative 
262WomanTail7MCNCysticNegative 
380WomanTail3.5MCNACysticNegativeWell
473ManTail1.6IPMNCysticNegative 
552WomanTail1.8IPMNCysticNegative 
657WomanHead1.4IPMNCysticNegative 
764WomanTail5MCNACysticNegativeWell
868WomanHead2.4MCNCysticNegative 
961WomanHead1PENSolidNegativeWell
1059WomanHead3.5ACSolidAtypicalModerate
1174ManTail3PENSolidAtypical 
1288ManHead2.8ACSolid (IE)AtypicalModerate
1365WomanHead2.5ACSolidAtypicalModerate
1460WomanHead3ACSolidNegativeModerate
1563ManHead2.1ACSolidAtypicalModerate
1678ManHead4.3ACSolidAtypicalPoor
1757WomanHead2.8ACSolidNegativeWell
1857ManTail2.3ACSolid (IE)AtypicalModerate
1943WomanTail1PENSolidAtypical 

Therefore, all 19 (19%) discordant cases among the 97 adequate EUS-FNA cases were false-negative cases. These cases included both SEs and IEs. Among the false-negative FNA cases, only 2 cases were due to a cytopathologic IE (2 of 19 cases; 11%), whereas the remaining cases (17 of 19 cases; 90%) were negative because of an SE. Both IE cases were originally diagnosed as “atypical cells present” on FNA, but demonstrated adenocarcinoma in the matched surgical resections (Fig. 2). Among the 17 cases of SE, 6 cases were diagnosed as adenocarcinoma, 4 cases were diagnosed as IPMN, 2 cases were diagnosed as MCN, 3 cases were diagnosed as pancreatic endocrine neoplasm, and 2 cases were diagnosed as MCNA in the matched surgical resection specimen (Table 4). Eight of 17 cases of SE were cystic tumors and 9 cases were solid pancreatic tumors. Seven of the 19 discordant cases had repeat FNA sampling, but the repeat cytology diagnoses were also false-negative results.

image

Figure 2. An example of 1 false-negative case resulting from interpretive error is shown. (A, B, and C) The original diagnosis was atypical cells present, the consensus cytology diagnosis was adenocarcinoma, and the surgical diagnosis was invasive adenocarcinoma (A, Diff-Quik stain, × 600; B, Papanicolaou stain, × 600; C, surgical resection stained with H & E, × 200).

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The 101 FNA cases were divided further into 2 groups including 26 cystic lesions and 75 solid lesions (Tables 1 and 4). Based on the definition from the previous description, the true-positive and true-negative cases as well as the false-positive and false-negative cases were determined (Table 1). The rate of SE in cystic lesions (8 of 24 cases; 33%) was significantly higher than that in solid lesions (9 of 73 cases; 12%) (P < .05).

Comparison of the False-Negative Rate and Other Parameters in Both Solid and Cystic Lesions by Pancreatic EUS-FNA

The 5 groups were defined to analyze the various parameters in cystic and/or solid lesions with IEs and/or technical SEs (Tables 2 and 5). In group 1, SEs and IEs were found in all cases (both cystic and solid lesions); in group 2, IEs were found in all cases; in group 3, SEs were found in all cases; in group 4, SEs were found in cystic lesions; and in group 5, SEs were found in solid lesions. The sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate, and accuracy of EUS-FNA in all 5 groups was calculated (Table 5).

Table 5. Sensitivity, Specificity, Accuracy, PPV, NPV, FPR, and FNR in Various Subgroups of Pancreatic EUS-FNA Cases With or Without Sampling Error
SubgroupsSensitivity, %Specificity, %PPV, %NPV, %FPR, %FNR, %Accuracy, %
  1. Abbreviations: EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; FNR, false-negative rate; FPR, false-positive rate; NPV, negative predictive value; PPV, positive predictive value.

  2. a

    Indicates that the rates were significantly different from those of other groups.

  3. b

    Indicates that the rates were significantly different between 2 labeled groups.

1751001005102580
297a10010091a03a98a
3771001005402382
447b1001005305367b
585b1001005501587b

In group 1 (all matched FNA cases) the false-negative rate was 25% (95% CI, 16%-36%), but the true accuracy was 80% (95% CI, 71%-87%). The sensitivity was 75% (95% CI, 64%-84%), but the specificity was 100% (95% CI, 76%-100%) (Table 5).

The false-negative rate in group 2 (IEs only for all lesions) decreased dramatically from 25% in group 1 to 3% in Group 2 (95% CI, 0%-12%), which was also significantly lower compared with group 3 (SEs only) at 23% (P < .01) (Table 5). The sensitivity 97% (95% CI, 88%-100%) and accuracy 98% (95% CI, 91%-100%) for group 2 demonstrated a greater increase compared with the sensitivity (77%) and accuracy (82%) for group 3 (P < .05) (Table 5).

The sensitivity (47%) and accuracy (67%) in group 4 (SEs in cystic lesions) was less than the sensitivity (85%) and accuracy (87%) in group 5 (SEs in solid lesions). This indicated that EUS-FNA of cystic lesions was less sensitive and accurate compared with that for solid lesions.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Using the surgical resection as the gold standard for diagnosis, we systematically studied the sensitivity, specificity, positive predictive value, negative predictive value, false-positive and false-negative rates, and accuracy of EUS-FNA diagnosis of pancreatic solid and/or cystic lesions performed at the University of Rochester from 2004 through 2010. We have confirmed previous studies[11] that indicated that pancreatic EUS-FNA has a very low false-positive rate (0%) (Table 5). The false-negative rate was relatively higher, with the majority of false-negative results found to be due to SE, but some were the result of IE (IE rate in group 2: 3% vs SE rate in group 3: 23%). The false-negative rate, sensitivity, and accuracy were significantly different when considering IE alone (group 2) compared with SE alone (group 3). In addition, we also confirmed that the frequency of SE (33%) in EUS-FNA of cystic lesions (group 4) was significantly higher than that in solid lesions (12%; Group 5). The sensitivity (47%) and accuracy (67%) for cystic lesions (group 4) were significantly lower than those in solid lesions (85% and 87%, respectively; group 5). The results of the current study demonstrate that a false-negative diagnosis is the primary concern in pancreatic EUS-FNA procedures.

As shown in previous studies, EUS has become one of the preferred imaging techniques in evaluating pancreatic solid lesions and has high sensitivity and specificity with a very low false-positive rate.[3-5] The majority of previous studies used clinical follow-up and radiologic imaging combined with surgical resection as the gold standard. Recently, Gleeson et al[12] used direct surgical resection after EUS-FNA as a gold standard to study the false-positive rate of EUS-FNA. They found that the false-positive and false-suspicious cases represented 7.2% of gastrointestinal EUS-FNA cases and the incidence of discordance was higher in nonpancreatic FNA cases (22 of 147 cases; 15%) than pancreatic FNA cases (5 of 230 cases; 2.2%). This study tried to correct the broadly accepted false-positive rate for EUS-FNA of approximately 0% to 1%. Siddiqui et al further showed that the false-positive rate of EUS-FNA diagnoses for solid pancreatic lesions was 3.8% (14 of 367 cases) when both suspicious and positive cytology findings were interpreted as malignant.[15] Using the surgical resection as the gold standard for diagnosis, we found no false-positive results in the current study (none of 101 cases). This result agrees with the previously accepted false-positive rate of 0% to 1%.[11] However, we noted that our pancreatic EUS-FNA cases had a higher false-negative rate 25% (95% CI, 16%-36%) in both solid and cystic lesions. The current study has further investigated the false-negative rate of EUS-FNA.

Studies of false-negative rates of pancreatic EUS-FNA are challenged by the lack of clinical follow-up and a way to prove negative EUS-FNA cases. In the current study, many benign and malignant pancreatic surgical resection cases were identified. This gave us the opportunity to use the surgical resection diagnosis as a gold standard to explore the false-negative rate and other parameters. However, limitations remain because many cases performed during the studied time period did not undergo resections. Based on this gold standard, the false-negative rate among solid lesions is 15% (group 5), which is lower than the 35% rate (range, 8%-84%) calculated from the previous meta-analysis of pancreatic solid lesions.[5, 8, 27, 28] To further study the causes of false-negative results at the study institution, the false-negative rate was calculated in 2 groups. In group 2, only those cases with an IE were used for analysis; in group 3, only cases with an SE were evaluated. We found that the false-negative rate (3%) caused by IE was significantly lower than that caused by SE (23%) (P = .003). This suggests that SE, rather than IE, is a major cause of higher false-negative findings. Because we included both solid and cystic lesions, we further examined the false-negative rate in these 2 groups separately (solid lesions in group 5 and cystic lesions in group 4). The false-negative rate among cystic lesions was significantly higher than that in solid lesions (53% vs 15%; P = .005). However, as mentioned earlier, there were 403 total negative pancreatic EUS-FNA cases during this time period. Only 19 cases were proven to be false-negative cases and 20 cases were found to be true-negative findings by comparing the surgical resection diagnosis. The true diagnoses of the remaining cases were unknown because the majority of negative cases do not go on to surgical resection. We attempted to find follow-up information for these negative EUS-FNA cases. Unfortunately, in most cases, no clinical follow-up information was available, which made the accurate examination of the true false-negative rate impossible. However, the real frequency of false-negative findings has to be within a maximum of 49% (19 of 39 cases) and minimum of 5% (19 of 403 cases). Although all cases with matched pancreatic EUS-FNA specimens and surgical resections were included in the current study, we can argue that the data still represent the relative ratio of IE and SE. Cytologic IE is likely less common because of accepted stringent criteria to make a positive cytology diagnosis.

The sensitivity, specificity, and accuracy of pancreatic EUS-FNA were also analyzed in various subgroups. The sensitivity (47%) and accuracy (67%) for cystic lesions (group 4) were significantly lower than those for solid lesions (group 5; 85% and 87%, respectively). A preoperative diagnosis of pancreatic cystic lesions by EUS-FNA remains a challenge. Multiple clinical and laboratory methods are usually used to improve the sensitivity and accuracy. Cystic fluid sent for amylase and carcinoembryonic antigen (CEA) measurement has shown variable and inconsistent accuracy rates.[8, 20, 25] Performing CEA levels on pancreatic cysts has demonstrated accuracy rates ranging from 42.9% to 86%.[8, 24, 29, 30] The cytologic diagnosis of cystic lesions with EUS-FNA has also been studied extensively with widely variable sensitivity reported.[13, 19-24] The sensitivity has been reported to range from 23% to 100% and specificity has been reported to range from 71% to 100%.[8, 13, 23] One meta-analysis by Thosani et al[25] showed that the pooled sensitivity and specificity in diagnosing mucinous cystic lesions were 63% and 88%, respectively, in 11 studies and 54% and 92%, respectively, in 4 prospective studies. The sensitivity in the current study (47%) was lower than these meta-analysis results because we restricted our cases to those with subsequent surgical resections. Brugge et al concluded that a CEA level from pancreatic mucinous cysts was more accurate than the cytology diagnosis (86% vs 58%), but less accurate in the setting of a malignant cyst (62% vs 75%).[24] Recently, Rogart et al reported that cyst wall puncture and FNA improved the diagnostic yield for mucinous cysts.[31] In addition, cytologic classification with high-grade epithelial atypia in cystic lesion FNA specimens demonstrated a higher prediction for malignancy and added value for the clinical evaluation of cystic lesions.[9, 32] However, the overall sensitivity of the EUS-FNA cytologic diagnosis of pancreatic cystic lesions is still low. More sensitive and specific techniques are needed and should be developed as new technologies emerge, such as molecular tests and confocal laser endomicroscopy.

Confocal laser endomicroscopy is a novel imaging technology in which a low-power laser illuminates and scans a single focal plane of the tissue.[33-35] This technique allows for the detection of the microscopic detail of the surface epithelium in pancreatic cysts. Further studies and development of this new technique may facilitate sampling the most suspicious area of a cyst.

Recently, molecular tests were reported that aid in the detection of malignant pancreatic cystic lesions.[36-41] In 1 small case study, the sensitivity, specificity, and positive predictive value of molecular diagnosis were 83%, 100%, and 100%, respectively, for a malignant cyst and 86%, 93%, and 95%, respectively, for a benign mucinous cyst.[38] Cystic fluids from 19 patients were studied for genetic mutations in 169 genes commonly altered in human cancers.[40] In addition, a larger number (113 cases) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, GNAS mutations were present in 66% of IPMNs and either KRAS or GNAS mutations could be identified in 96%. It is interesting to note that all 44 serous cystadenomas were GNAS and KRAS wild-type. GNAS/KRAS mutations reliably distinguished IPMNs from serous cystadenomas with a sensitivity of 96% and a specificity of 100%.[40] From the review, KRAS had a low sensitivity (range, 11%-57%) and a high specificity (range, 93%-100%) for diagnosing mucinous cysts. The specificity (range, 71%-93%) and sensitivity (range, 20%-53%) decreased further when KRAS mutations were used for the determination of malignancy.[41] Emerging molecular tests, including next-generation sequencing and droplet polymerase chain reaction, will hopefully shed light on improving the sensitivity, specificity, and false-negative rate.

Conclusions

In the current study, all analyses were based on matched cytology and surgical resection data. We found that a pancreatic EUS-FNA cytologic diagnosis had a high specificity and accuracy for solid lesions and lower sensitivity, specificity, and accuracy for cystic lesions. The major cause of a false-negative result on EUS-FNA was due to SE than IE. We suggest that combined cytologic diagnosis with new sensitive molecular tests, CEA measurement, or advanced confocal laser endomicroscopy could dramatically improve the false-negative rate for cystic lesions in the future.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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